Substituted [1,2,4]triazolo[4,3-a]pyrazines as ion channel modulators

ABSTRACT

The present invention is directed to, in part, fused heteroaryl compounds of Formula (II-II): 
                         
and compositions thereof, useful for preventing and/or treating a disease or condition relating to aberrant function of a voltage-gated, sodium ion channel, for example, abnormal late/persistent sodium current. Methods of treating a disease or condition relating to aberrant function of a sodium ion channel including neurological disorders (e.g., Dravet syndrome, epilepsy), pain, and neuromuscular disorders are also provided herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Patent Application Nos. 62/940,489, filed Nov. 26, 2019; 62/940,502 filed Nov. 26, 2019; and 62/940,503 filed Nov. 26, 2019, the entire contents of which are incorporated by reference herein.

BACKGROUND

Sodium ion (Na+) channels primarily open in a transient manner and are quickly inactivated, thereby generating a fast Na+ current to initiate the action potential. The late or persistent sodium current (INaL) is a sustained component of the fast Na+ current of cardiac myocytes and neurons. Many common neurological and cardiac conditions are associated with abnormal INaL enhancement, which contributes to the pathogenesis of both electrical and contractile dysfunction in mammals (see, e.g., Pharmacol Ther (2008) 119:326-339).

Accordingly, pharmaceutical compounds that selectively modulate sodium channel activity, e.g., abnormal INaL, are useful in treating such disease states.

SUMMARY

Described herein are fused heteroaryl compounds and compositions useful for preventing and/or treating a disease, disorder, or condition, e.g., a disease, disorder, or condition relating to aberrant function of a sodium ion channel, e.g., abnormal late/persistent sodium current (INaL).

Thus, in one aspect, provided herein is a compound having the Formula I-I:

or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹ is halo;     -   R² is C₁₋₄haloalkyl;     -   R³ and R⁴ are each independently selected from the group         consisting of hydrogen, C₁₋₄ alkyl, and C₃₋₆carbocyclyl; or R³         and R⁴ together with the carbon attached to R³ and R⁴ form a         C₃₋₆ carbocyclyl;     -   R⁵ is C₁₋₄alkyl; and     -   t is 0or 1.

In another aspect, provided herein is a compound having the Formula II-I:

or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹ is halo;     -   R² is C₁₋₄haloalkyl;     -   R³ and R⁴ are each independently hydrogen or C₁₋₄alkyl; or R³         and R⁴ together with the carbon attached to R³ and R⁴ form a         C₃₋₆carbocyclyl;     -   R⁵ is C₁₋₄alkyl; and     -   t is 0or 1.

In another aspect, provided herein is a compound having the Formula II-II:

or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹ is halo;     -   R² is C₁₋₄haloalkyl;     -   R³ and R⁴ are each independently hydrogen or C₁₋₄alkyl; or R³         and R⁴ together with the carbon attached to R³ and R⁴ form a         C₃₋₆carbocyclyl;     -   R⁵ is C₁₋₄alkyl; and     -   t is 0or 1.

In another aspect, provided herein is a compound of Formula (III-I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   L is C₁₋₆alkyl;     -   R¹ is selected from the group consisting of

CF₃, monocyclic C₃₋₆ cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more R^(a);

-   -   R² is selected from the group consisting of hydrogen,         C₁₋₄haloalkyl, and monocyclic C₃₋₆ cycloalkyl optionally         substituted with one or more R^(b);     -   R³ is selected from the group consisting of hydrogen, C₁₋₄alkyl,         and C₁₋₄haloalkyl;     -   R⁴ is hydrogen or C₁₋₄alkyl;     -   R⁵ is selected from the group consisting of halo, C₃₋₆         cycloalkyl, and C₁₋₄alkyl optionally substituted with O—C₁₋₄         alkyl or O—C₃₋₆ cycloalkyl;     -   R⁶ is C₁₋₄alkyl or C₁₋₄haloalkyl, wherein the C₁₋₄alkyl or         C₁₋₄haloalkyl is each substituted with OR^(c);     -   m is 0, 1, or 2;     -   R^(a) and R^(b) are each independently selected from the group         consisting of halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and         C₁₋₄haloalkoxy; and     -   R^(c) is C₁₋₄alkyl optionally substituted with C₃₋₆ cycloalkyl         or phenyl, or C₃₋₆ cycloalkyl.

In another aspect, provided herein is a compound of Formula (III-II):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R⁷ is a monocyclic C₃₋₆ cycloalkyl substituted with one or more         R^(a);     -   R⁵ is selected from the group consisting of halo, C₃₋₆         cycloalkyl, and C₁₋₄alkyl optionally substituted with O—C₁₋₄         alkyl or O—C₃₋₆ cycloalkyl; R⁶ is C₁₋₄alkyl or C₁₋₄haloalkyl,         wherein the C₁₋₄alkyl or C₁₋₄haloalkyl is each substituted with         OR^(c);     -   m is 0, 1, or 2; R^(a) is selected from the group consisting of         halo, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, and C₁₋₄ haloalkoxy;         and     -   R^(c) is C₁₋₄alkyl optionally substituted with C₃₋₆ cycloalkyl         or phenyl, or C₃₋₆ cycloalkyl.

In another aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

In one aspect, provided herein is a method of treating a condition relating to aberrant function of a sodium ion channel in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the condition is a neurological or psychiatric disorder. In some embodiments, the condition is epilepsy or an epilepsy syndrome. In some embodiments, the condition is a genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, the condition is a pediatric epilepsy or a pediatric epilepsy syndrome. In some embodiments, the condition is epileptic encephalopathy.

In some embodiments, the epileptic encephalopathy is selected from the group consisting of Dravet syndrome, infantile spasms, or Lennox-Gastaut syndrome. In some embodiments, the condition is selected from the group consisting of epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

In another aspect, provided herein is a method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. Also provided herein is a method of treating a pain, wherein the method comprises administering to a subject in need thereof a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

In another aspect, methods of preventing or treating trigeminal autonomic cephalalgia (e.g., paroxysmal hemicrania, hemicrania continua, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA), and long-lasting autonomic symptoms with hemicrania) are provided. Also provided herein are methods of preventing or treating a cranial neuropathy (e.g., bell palsy, microvascular cranial nerve palsy, third nerve palsy, fourth nerve palsy, and sixth nerve palsy) or multiple cranial neuropathies (MCN). In certain embodiments, methods of preventing or treating a migraine (e.g., migraine without aura, migraine with aura, familial hemiplegic migraine type 1 (FHM1), familial hemiplegic migraine type 2 (FHM2), familial hemiplegic migraine type 4 (FHM4), and sporadic hemiplegic migraine (SHM)) are provided. In some other embodiments, provided herein are methods of preventing or treating cortical spreading depression (CDC).

In one aspect, the present disclosure provides a method of treating or preventing trigeminal autonomic cephalalgia (TAC) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, wherein the TAC is selected from the group consisting of paroxysmal hemicrania, hemicrania continua, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA), and long-lasting autonomic symptoms with hemicrania.

In another aspect, provided herein is a method of treating or preventing a migraine in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, wherein the migraine is selected from the group consisting of migraine without aura, migraine with aura, familial hemiplegic migraine type 1 (FHM1), familial hemiplegic migraine type 2 (FHM2), familial hemiplegic migraine type 4 (FHM4), and sporadic hemiplegic migraine (SHM).

In another aspect, the present disclosure provides a method of treating or preventing cortical spreading depression (CSD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

In another aspect, the present disclosure provides a method of treating or preventing a cranial neuropathy or multiple cranial neuropathies (MCN) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

Other objects and advantages will become apparent to those skilled in the art from consideration of the ensuing Detailed Description, Examples, and Claims.

DETAILED DESCRIPTION

As generally described herein, the present invention provides compounds and compositions useful for preventing and/or treating a disease, disorder, or condition described herein, e.g., a disease, disorder, or condition relating to aberrant function of a sodium ion channel, such as abnormal late sodium current (INaL). Exemplary diseases, disorders, or conditions include a neurological disorder (e.g., epilepsy or an epilepsy syndrome, a neurodevelopmental disorder or a neuromuscular disorder), a psychiatric disorder, pain, or a gastrointestinal disorder.

Definitions

Chemical Definitions

Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March 's Advanced Organic Chemistry, _(5h) Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3^(rd) Edition, Cambridge University Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound.

In certain embodiments, the enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

Compound described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including ¹H, ²H (D or deuterium), and ³H (T or tritium); C may be in any isotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopic form, including ¹⁶O and ¹⁸O; F may be in any isotopic form, including ¹⁸F and ¹⁹F; and the like.

The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. When describing the invention, which may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. The articles “a” and “an” may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue.

When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C₁₋₆ alkyl” is intended to encompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆, C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

As used herein, “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms (“C₁₋₂o alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C₁₋₁₀ alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C_(1-s) alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C₁₇ alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C₁_5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). Examples of C₁₋₆ alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

As used herein, “alkylene” refers to a divalent radical of an alkyl group. When a range or number of carbons is provided for a particular “alkylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Alkylene” groups may be substituted or unsubstituted with one or more substituents as described herein.

As used herein, “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀ carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C₃₋₇ carbocycyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include, without limitation, cyclopropyl (C₃),cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like. Exemplary C₃_8 carbocyclyl groups include, without limitation, the aforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclyl groups include, without limitation, the aforementioned C₃₋₈ carbocyclyl groups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.

The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C₄₋₈cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes.

As used herein, “C₃₋₆ monocyclic cycloalkyl” or “monocyclic C₃₋₆ cycloalkyl” refers to a 3- to 7-membered monocyclic hydrocarbon ring system that is saturated. 3- to 7-membered monocyclic cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Where specified as being optionally substituted or substituted, substituents on a cycloalkyl (e.g., in the case of an optionally substituted cycloalkyl) may be present on any substitutable position and, include, e.g., the position at which the cycloalkyl group is attached.

As used herein, “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” may be used interchangeably.

In some embodiments, a heterocyclyl group is a 4-7 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“4-7 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

Examples of saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl and tetrahydropyrimidinyl. Where specified as being optionally substituted or substituted, substituents on a heterocyclyl (e.g., in the case of an optionally substituted heterocyclyl) may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl group is attached. “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl; carbocyclyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine (fluoro, —F), chlorine (chloro, —C₁), bromine (bromo, —Br), and iodine (iodo, —I). In certain embodiments, the halo group is either fluoro or chloro.

The term “haloalkyl” includes mono, poly, and perhaloalkyl groups substituted with one or more halogen atoms where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.

The term “alkoxy,” as used herein, refers to an alkyl group which is attached to another moiety via an oxygen atom (—O(alkyl)). Non-limiting examples include e.g., methoxy, ethoxy, propoxy, and butoxy.

“Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., but are not limited to —OCHCF₂ or —OCF₃.

In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.

Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms. Exemplary nitrogen atom substitutents include, but are not limited to, hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc), —SOR^(cc), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), —P(═O)₂R^(cc), —P(═O)(Raa)₂,—P(=O)₂N(R^(cc))₂ P(=O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(cc) groups attached to a nitrogen atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are as defined above.

These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.

Other Definitions

As used herein, “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

As used herein, “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C₁₋₄alkyl)₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

As used herein, a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment”).

As used herein, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment.

As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

Compounds

In one aspect, provided herein is a compound having the Formula I-I:

or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹ is halo;     -   R² is C₁₋₄haloalkyl;     -   R³ and R⁴ are each independently selected from the group         consisting of hydrogen, C₁₋₄ alkyl, and C₃₋₆carbocyclyl; or R³         and R⁴ together with the carbon attached to R³ and R⁴ form a         C₃₋₆ carbocyclyl;     -   R⁵ is C₁₋₄alkyl; and     -   t is 0or 1.

In some embodiments, the compound is a compound of Formula I-I-a:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula I-I-a1 or Formula I-I-a2:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula I-I-b:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula 1-1-b1 or Formula I-I-b2

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is fluoro. In some embodiments, R² is CF₃. In some embodiments, R³ and R⁴ are each C₁₋₄alkyl. In some embodiments, R³ and R⁴ are each methyl. In some embodiments, R³ is hydrogen and R⁴ is C₃₋₆carbocyclyl. In some embodiments, R³ is hydrogen and R⁴ is cyclopropyl. In some embodiments, R³ and R⁴ together with the carbon attached to R³ and R⁴ form cyclobutyl. In some embodiments, R⁵ is methyl or ethyl. In some embodiments, t is 1.. In some embodiments, t is 0.

In some embodiments, the compound of Formula I-I is selected from the group consisting of

pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a compound having the Formula II-I.

or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹ is halo;     -   R2 is C₁₋₄haloalkyl;     -   R³ and R⁴ are each independently hydrogen or C₁₋₄alkyl; or R³         and R⁴ together with the carbon attached to R³ and R⁴ form a         C₃₋₆carbocyclyl;     -   R⁵ is C₁₋₄alkyl; and     -   t is 0or 1.

In some embodiments, the compound is a compound of Formula II-I-a:

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is fluoro. In some embodiments, R² is CF₃. In some embodiments, R³ and R⁴ are each hydrogen. In some embodiments, R³ is hydrogen and R⁴ is methyl. In some embodiments, R⁵ is methyl. In some embodiments, t is 1.

In some embodiments, the compound of Formula II-I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a compound having the Formula II-II:

or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹ is halo;     -   R² is C₁₋₄haloalkyl;     -   R³ and R⁴ are each independently hydrogen or C₁₋₄alkyl; or R³         and R⁴ together with the carbon attached to R³ and R⁴ form a         C₃₋₆carbocyclyl;     -   R⁵ is C₁₋₄alkyl; and     -   t is 0or 1.

In some embodiments, the compound is a compound of Formula II-II-a:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula II-II-b:

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is fluoro. In some embodiments, R² is CF₃. In some embodiments, R³ and R⁴ are each hydrogen. In some embodiments, R³ is hydrogen and R⁴ is methyl. In some embodiments, R³ and R⁴ are each methyl. In some embodiments, R³ and R⁴ together with the carbon attached to R³ and R⁴ form cyclobutyl. In some embodiments, R⁵ is methyl or ethyl. In some embodiments, t is 1. In some embodiments, t is 0.

In some embodiments, the compound of Formula II-II is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a compound of Formula (III-I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   L is C₁-6alkyl;

R¹ is selected from the group consisting of

CF₃, monocyclic C₃₋₆ cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more R^(a);

-   -   R² is selected from the group consisting of hydrogen,         C₁₋₄haloalkyl, and monocyclic C₃₋₆ cycloalkyl optionally         substituted with one or more R^(b);     -   R³ is selected from the group consisting of hydrogen, C₁₋₄alkyl,         and C₁₋₄haloalkyl;     -   R⁴ is hydrogen or C₁₋₄alkyl;     -   R⁵ is selected from the group consisting of halo, C₃₋₆         cycloalkyl, and C₁₋₄alkyl optionally substituted with O—C₁₋₄         alkyl or O—C₃₋₆ cycloalkyl;     -   R⁶ is C₁₋₄alkyl or C₁₋₄haloalkyl, wherein the C₁₋₄alkyl or         C₁₋₄haloalkyl is each substituted with OR^(c);     -   m is 0, 1, or 2;     -   R^(a) and R^(b) are each independently selected from the group         consisting of halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and         C₁₋₄haloalkoxy; and     -   R^(c) is C₁₋₄alkyl optionally substituted with C₃₋₆ cycloalkyl         or phenyl, or C₃₋₆ cycloalkyl.

In some embodiments, the compound is a compound of Formlula (ITT-I-a):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (III-I-b):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (III-I-c):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (III-I-d):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (III-I-e):

or a pharmaceutically acceptable salt thereof.

In some embodiments, L is —CH₂— or —CHCH₃—.

In some embodiments, R² is C₁₋₄haloalkyl. In some embodiments, R² is CF₃.

In some embodiments, R³ and R⁴ are both hydrogen.

In some embodiments, R⁵ is C_(1.4)alkyl. In some embodiments, R⁵ is methyl.

In some embodiments, m is 1.

In some embodiments, R⁶ is C₁₋₄haloalkyl substituted with OR^(c). In some embodiments, R⁶ is CF₂OR^(c). In some embodiments, R is C₁₋₄alkyl. In some embodiments, R is methyl or ethyl.

In some embodiments, the compound of Formula III-I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a compound of Formula (IR—I.):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R⁷ is a monocyclic C₃₋₆ cycloalkyl substituted with one or more         R^(a);     -   R⁵ is selected from the group consisting of halo, C₃₋₆         cycloalkyl, and C₁₋₄alkyl optionally substituted with 0-C₁₋₄         alkyl or O—C₃₋₆ cycloalkyl;     -   R⁶ is C₁₋₄alkyl or C₁₋₄haloalkyl, wherein the C₁₋₄alkyl or         C₁₋₄haloalkyl is each substituted with OR^(c);     -   m is 0, 1, or 2;     -   R^(a) is selected from the group consisting of halo, C₁₋₄alkyl,         C₁₋₄haloalkyl, C₁₋₄alkoxy, and C₁₋₄ haloalkoxy; and     -   R^(c) is C₁₋₄alkyl optionally substituted with C₃₋₆ cycloalkyl         or phenyl, or C₃₋₆ cycloalkyl.

In some embodiments, the compound is a compound of Formula (III-II-a):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (III-II-b):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (ITT-TI-c):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (III-II-d):

or a pharmaceutically acceptable salt thereof.

In some embodiments the compound is a compound of Formula (III-II-e):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (III-II-f):

wherein n is 0, 1, 2, 3, 4, or 5; or a pharmaceutically acceptable salt thereof.

-   -   In some embodiments, R⁷ is cyclopropyl.     -   In some embodiments, R⁵ is C_(1.4)alkyl. In some embodiments, R⁵         is methyl.     -   In some embodiments, m is 1.

In some embodiments, R⁶ is C₁₋₄haloalkyl substituted with OR^(c). In some embodiments, R⁶ is CF₂OR^(c). In some embodiments, R is C₁₋₄alkyl. In some embodiments, R^(c) is methyl.

In some embodiments, the compound of Formula III-II is selected the group consisting of:

or a pharmaceutically acceptable salt thereof.

Also provided herein is a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof. Pharmaceutical Compositions and Routes of Administration

Compounds provided in accordance with the present invention are usually administered in the form of pharmaceutical compositions. This invention therefore provides pharmaceutical compositions that contain, as the active ingredient, one or more of the compounds described herein, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes, Eds.)

The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.

One mode for administration is parenteral, particularly by injection. The forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection, but less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating a compound according to the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Oral administration is another route for administration of compounds in accordance with the invention. Administration may be via capsule or enteric coated tablets, or the like. In making the pharmaceutical compositions that include at least one compound described herein, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present invention employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

The compositions are preferably formulated in a unit dosage form. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains from 1 mg to 2 g of a compound described herein, and for parenteral administration, preferably from 0.1 to 700 mg of a compound a compound described herein. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

In some embodiments, a pharmaceutical composition comprises a disclosed compound, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Methods of Treatment Compounds and compositions described herein are generally useful for the modulating the activity of sodium channels and are useful in treating conditions relating to aberrant function of a sodium channel ion channel, e.g., abnormal late sodium (INaL) current. In some embodiments, a compound provided by the present invention is effective in the treatment of epilepsy or an epilepsy syndrome, a neurodevelopmental disorder, pain, or a neuromuscular disorder. In some embodiments, a compound provided by the present invention is effective in the treatment of neuropathy such as cranial neuropathy and pain such as migraines, trigeminal autonomic cephalalgias, and cortical spreading depression. A provided compound, pharmaceutically acceptable salt thereof, or composition may also modulate all sodium ion channels, or may be specific to only one or a plurality of sodium ion channels, e.g., Nav 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and/or 1.9.

In typical embodiments, the present invention is intended to encompass the compounds disclosed herein, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomeric forms, polymorphs, and prodrugs of such compounds. In some embodiments, the present invention includes a pharmaceutically acceptable addition salt, a pharmaceutically acceptable ester, a solvate (e.g., hydrate) of an addition salt, a tautomeric form, a polymorph, an enantiomer, a mixture of enantiomers, a stereoisomer or mixture of stereoisomers (pure or as a racemic or non-racemic mixture) of a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II).

Epilepsy and Epilepsy Syndromes

The compounds described herein are useful in the treatment of epilepsy and epilepsy syndromes. Epilepsy is a CNS disorder in which nerve cell activity in the brain becomes disrupted, causing seizures or periods of unusual behavior, sensations and sometimes loss of consciousness. Seizure symptoms will vary widely, from a simple blank stare for a few seconds to repeated twitching of their arms or legs during a seizure.

Epilepsy may involve a generalized seizure or a partial or focal seizure. All areas of the brain are involved in a generalized seizure. A person experiencing a generalized seizure may cry out or make some sound, stiffen for several seconds to a minute a then have rhythmic movements of the arms and legs. The eyes are generally open, the person may appear not to be breathing and may actually turn blue. The return to consciousness is gradual and the person maybe confused from minutes to hours. There are six main types of generalized seizures: tonic-clonic, tonic, clonic, myoclonic, absence, and atonic seizures. In a partial or focal seizure, only part of the brain is involved, so only part of the body is affected. Depending on the part of the brain having abnormal electrical activity, symptoms may vary.

Epilepsy, as described herein, includes a generalized, partial, complex partial, tonic clonic, clonic, tonic, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.

The compounds described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II) may also be useful in the treatment of epilepsy syndromes. Severe syndromes with diffuse brain dysfunction caused, at least partly, by some aspect of epilepsy, are also referred to as epileptic encephalopathies. These are associated with frequent seizures that are resistant to treatment and severe cognitive dysfunction, for instance West syndrome.

In some embodiments, the epilepsy syndrome comprises an epileptic encephalopathy, such as Dravet syndrome, Angelman syndrome, CDKL5 disorder, frontal lobe epilepsy, infantile spasms, West's syndrome, Juvenile Myoclonic Epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency.

In some embodiments, the epilepsy or epilepsy syndrome is a genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, epilepsy or an epilepsy syndrome comprises epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

In some embodiments, the methods described herein further comprise identifying a subject having epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized Epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy) prior to administration of a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II).

In one aspect, the present invention features a method of treating epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized Epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy) comprising administering to a subject in need thereof a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II). or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

A compound of the present invention (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II) may also be used to treat an epileptic encephalopathy, wherein the subject has a mutation in one or more of ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT 1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAPI, SZT2, TBC1D24, and WWOX.

In some embodiments, the methods described herein further comprise identifying a subject having a mutation in one or more of ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAPI, SZT2, TBC1D24, and WWOX prior to administration of a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II).

Neurodevelopmental Disorders

The compounds described herein may be useful in the treatment of a neurodevelopmental disorder. In some embodiments, the neurodevelopmental disorder comprises autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dupl5q syndrome, 22ql3.3 Deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder with epilepsy. In some embodiments, the methods described herein further comprise identifying a subject having a neurodevelopmental disorder (e.g., autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dupl5q syndrome, 22ql3.3 Deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder with epilepsy) prior to administration of a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II).

In one aspect, the present invention features a method of treating a neurodevelopmental disorder (e.g., autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dupl5q syndrome, 22ql3.3 Deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder with epilepsy) comprising administering to a subject in need thereof a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II).

Pain

The compounds described herein may be useful in the treatment of pain. In some embodiments, the pain comprises neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, or a related headache disorder. In some embodiments, the methods described herein further comprise identifying a subject having pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, or a related headache disorder) prior to administration of a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II).

In one aspect, the present invention features a method of treating pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, or a related headache disorder) comprising administering to a subject in need thereof a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II).

Neuromuscular Disorders

The compounds described herein may be useful in the treatment of a neuromuscular disorder. In some embodiments, the neuromuscular disorder comprises amyotrophic lateral sclerosis, multiple sclerosism, myotonia, paramyotonia congenita, potassium-aggravated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation. In some embodiments, the methods described herein further comprise identifying a subject having a neuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiple sclerosism, myotonia, paramyotonia congenita, potassium-aggravated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation) prior to administration of a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II).

In one aspect, the present invention features a method of treating a neuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiple sclerosism, myotonia, paramyotonia congenita, potassium-aggravated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation) comprising administering to a subject in need thereof a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II).

Trigeminal Autonomic Cephalalgia

The compounds described herein are useful in the treatment of trigeminal autonomic cephalalgias (TACs). TACs are a group of primary headaches characterized by unilaterality of pain, a relatively short duration of symptoms, and associated ipsilateral cranial autonomic signs.

TACs may include cluster headache (CH), paroxysmal hemicrania (PH), hemicrania continua (HC), short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA), and long-lasting autonomic symptoms with hemicrania (LASH). Despite their common elements, the trigeminal autonomic cephalalgias differ, e.g., in attack duration and frequency and in the response to therapy.

In some embodiments, the present invention provides a method of treating PH, HC, SUNCT, SUNA, and/or LASH using a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the present invention provides a method of treating SUNCT using a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the present invention provides a method of treating SUNA using a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

In some embodiments, the present invention provides a method of treating TAC (e.g., PH, HC, SUNCT, SUNA, or LASH) comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

In one aspect, provided herein is a method of treating or preventing trigeminal autonomic cephalalgia (TAC) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, wherein the TAC is selected from the group consisting of paroxysmal hemicrania, hemicrania continua, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA), and long-lasting autonomic symptoms with hemicrania.

In some embodiments, the subject may have an inadequate response to at least one medication (e.g., lidocaine, triptans, lamotrigine, topiramate, or gabapentin, or any combinations thereof) used for the treatment of a TAC (e.g., PH, HC, SUNCT, SUNA, or LASH).

In some embodiments, the methods described herein further comprise identifying a subject having a TAC (e.g., PH, CH, SUNCT, SUNA, or LASH) prior to the administration of a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

Migraines

The compounds described herein are useful in the treatment of migraines. Migraine is a primary headache disorder characterized by recurrent headaches that are moderate to severe. As described herein, a migraine may be migraine without aura, migraine with aura, hemiplegic migraine, familial hemiplegic migraine (FHM), familial hemiplegic migraine type 1 (FHM1), familial hemiplegic migraine type 2 (FHM2), familial hemiplegic migraine type 3 (FHM3), familial hemiplegic migraine type 4 (FHM4), and sporadic hemiplegic migraine (SHM).

In some embodiments, the present invention provides a method of treating migraine without aura, migraine with aura, hemiplegic migraine, FHM, FHM1, FHM2, FHM3, FHM4, and/or SHM using a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the present invention provides a method of treating migraine without aura, migraine with aura, FHM1, FHM2, FHM4, and/or SHM using a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the present invention provides a method of treating migraine without aura using a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the present invention provides a method of treating migraine with aura using a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the present invention provides a method of treating FHM1, FHM2, and/or FHM4 using a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the present invention provides a method of treating SHM using a a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

In some embodiments, the present invention provides a method of treating migraine (e.g., migraine without aura, migraine with aura, FHM1, FHM2, FHM4, or SHM) comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

In another aspect, the present disclosure provides a method of treating or preventing a migraine in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, wherein the migraine is selected from the group consisting of migraine without aura, migraine with aura, familial hemiplegic migraine type 1 (FHM1), familial hemiplegic migraine type 2 (FHM2), familial hemiplegic migraine type 4 (FHM4), and sporadic hemiplegic migraine (SHM).

In some embodiments, the subject has an inadequate response to at least one medication for the treatment of a migraine (e.g., migraine without aura, migraine with aura, FHM1, FHM2, FHM4, or SHM).

In some embodiments, the methods described herein further comprise identifying a subject having a migraine (e.g., migraine without aura, migraine with aura, FHM1, FHM2, FHM4, or SHM) prior to the administration of a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

Cortical Spreading Depression

The compounds described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, are useful in the treatment of cortical spreading depression (CSD). CSD is a wave of sustained depolarization (neuronal inactivation) moving through intact brain tissue and involved in, for example, brain ischemia, migraine aura, and seizures.

In some embodiments, the present invention provides a method of treating CSD using a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the present invention provides a method of treating CSD comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

In another aspect, provided herein is a method of treating or preventing cortical spreading depression (CSD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein

In some embodiments, the subject may have an inadequate response to at least one medication for the treatment of CSD.

In some embodiments, the methods described herein further comprise identifying a subject having a CSD prior to the administration of a compound described herein.

Cranial Neuropathy

The compounds described herein are useful in the treatment of cranial neuropathy. Neuropathy is a disorder of nerve damage and affects the ability to feel and move. When nerves in the brain or brainstem are affected, it is called cranial neuropathy. The cranial nerves are those that arise directly from the brain or brainstem and often affect areas like the face and eyes. Cranial neuropathies include Bell's palsy, microvascular cranial nerve palsy, third nerve palsy, fourth nerve palsy, and sixth nerve palsy. When several different cranial nerves are affected, it is called multiple cranial neuropathies (MCN).

In some embodiments, the present invention provides a method of treating cranial neuropathy (e.g., Bell's palsy, microvascular cranial nerve palsy, third nerve palsy, fourth nerve palsy, or sixth nerve palsy) or MCN comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

Also provided herein is a method of treating or preventing cranial neuropathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, wherein the cranial neuropathy is selected from the group consisting of bell palsy, microvascular cranial nerve palsy, third nerve palsy, fourth nerve palsy, and sixth nerve palsy.

In some embodiments, the subject may have an inadequate response to at least one medication for the treatment of cranial neuropathy (e.g., Bell's palsy, microvascular cranial nerve palsy, third nerve palsy, fourth nerve palsy, or sixth nerve palsy) or MCN.

In some embodiments, the methods described herein further comprise identifying a subject having a cranial neuropathy (e.g., Bell's palsy, microvascular cranial nerve palsy, third nerve palsy, fourth nerve palsy, or sixth nerve palsy) or MCN prior to the administration of a compound described herein (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

Other Disorders

In some embodiments, a compound of the present invention (e.g., a compound of Formula I-I, II-I, II-II, III-I, III-II) may have appropriate pharmacokinetic properties such that they may be active with regard to the central and/or peripheral nervous system. In some embodiments, the compounds provided herein are used to treat a cardiovascular disease such as atrial and ventricular arrhythmias, including atrial fibrillation, Prinzmetal's (variant) angina, stable angina, unstable angina, ischemia and reperfusion injury in cardiac, kidney, liver and the brain, exercise induced angina, pulmonary hypertension, congestive heart disease including diastolic and systolic heart failure, recurrent ischemia, cerebral ischemia, stroke, renal ischemia, ischemia associated with organ transplant, acute coronary syndrome, peripheral arterial disease, intermittent claudication, and myocardial infarction. In some embodiments, the compounds provided herein may be used in the treatment of diseases affecting the neuromuscular system resulting in itching, seizures, or paralysis, or in the treatment of diabetes or reduced insulin sensitivity, and disease states related to diabetes, such as diabetic peripheral neuropathy. In some embodiments, a disclosed method comprises administering the pharmaceutical composition.

In some embodiments, provided herein is a method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein.

Combination Therapy

A compound or composition described herein (e.g., for use in modulating a sodium ion channel, e.g., the late sodium (INaL) current) may be administered in combination with another agent or therapy. A subject to be administered a compound disclosed herein may have a disease, disorder, or condition, or a symptom thereof, that would benefit from treatment with another agent or therapy. These diseases or conditions can relate to epilepsy or an epilepsy syndrome, a neurodevelopmental disorder, pain, or a neuromuscular disorder.

Antiepilepsy Agents

Anti-epilepsy agents include brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbezepine, permpanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate, valproic acid, vigabatrin, zonisamide, and cannabidiol.

Cardiovascular Agent Combination Therapy

Cardiovascular related diseases or conditions that can benefit from a combination treatment of the sodium channel blockers of the invention with other therapeutic agents include, without limitation, angina including stable angina, unstable angina (UA), exercised-induced angina, variant angina, arrhythmias, intermittent claudication, myocardial infarction including non-STE myocardial infarction (NSTEMI), pulmonary hypertension including pulmonary arterial hypertension, heart failure including congestive (or chronic) heart failure and diastolic heart failure and heart failure with preserved ejection fraction (diastolic dysfunction), acute heart failure, or recurrent ischemia.

Therapeutic agents suitable for treating cardiovascular related diseases or conditions include anti-anginals, heart failure agents, antithrombotic agents, antiarrhythmic agents, antihypertensive agents, and lipid lowering agents.

The co-administration of the sodium channel blockers of the invention with therapeutic agents suitable for treating cardiovascular related conditions allows enhancement in the standard of care therapy the patient is currently receiving.

Anti-Anginals

Anti-anginals include beta-blockers, calcium channel blockers, and nitrates. Beta blockers reduce the heart's need for oxygen by reducing its workload resulting in a decreased heart rate and less vigorous heart contraction. Examples of beta-blockers include acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone), bisoprolol/hydrochlorothiazide (Ziac), bisoprolol (Zebeta), carteolol (Cartrol), esmolol (Brevibloc), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), and timolol (Blocadren).

Nitrates dilate the arteries and veins thereby increasing coronary blood flow and decreasing blood pressure. Examples of nitrates include nitroglycerin, nitrate patches, isosorbide dinitrate, and isosorbide-5-mononitrate.

Calcium channel blockers prevent the normal flow of calcium into the cells of the heart and blood vessels causing the blood vessels to relax thereby increasing the supply of blood and oxygen to the heart. Examples of calcium channel blockers include amlodipine (Norvasc, Lotrel), bepridil (Vascor), diltiazem (Cardizem, Tiazac), felodipine (Plendil), nifedipine (Adalat, Procardia), nimodipine (Nimotop), nisoldipine (Sular), verapamil (Calan, Isoptin, Verelan), and nicardipine.

Heart Failure Agents

Agents used to treat heart failure include diuretics, ACE inhibitors, vasodilators, and cardiac glycosides. Diuretics eliminate excess fluids in the tissues and circulation thereby relieving many of the symptoms of heart failure. Examples of diuretics include hydrochlorothiazide, metolazone (Zaroxolyn), furosemide (Lasix), bumetanide (Bumex), spironolactone (Aldactone), and eplerenone (lnspra).

Angiotensin converting enzyme (ACE) inhibitors reduce the workload on the heart by expanding the blood vessels and decreasing resistance to blood flow. Examples of ACE inhibitors include benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik).

Vasodilators reduce pressure on the blood vessels by making them relax and expand. Examples of vasodilators include hydralazine, diazoxide, prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassium channel activators, and calcium channel blockers also act as vasodilators.

Cardiac glycosides are compounds that increase the force of the heart's contractions. These compounds strengthen the pumping capacity of the heart and improve irregular heartbeat activity. Examples of cardiac glycosides include digitalis, digoxin, and digitoxin.

Antithrombotic Agents

Antithrombotics inhibit the clotting ability of the blood. There are three main types of antithrombotics—platelet inhibitors, anticoagulants, and thrombolytic agents.

Platelet inhibitors inhibit the clotting activity of platelets, thereby reducing clotting in the arteries. Examples of platelet inhibitors include acetylsalicylic acid (aspirin), ticlopidine, clopidogrel (plavix), dipyridamole, cilostazol, persantine sulfinpyrazone, dipyridamole, indomethacin, and glycoprotein IIb/IIIa inhibitors, such as abciximab, tirofiban, and eptifibatide (Integrelin). Beta blockers and calcium channel blockers also have a platelet-inhibiting effect.

Anticoagulants prevent blood clots from growing larger and prevent the formation of new clots. Examples of anticoagulants include bivalirudin (Angiomax), warfarin (Coumadin), unfractionated heparin, low molecular weight heparin, danaparoid, lepirudin, and argatroban.

Thrombolytic agents act to break down an existing blood clot. Examples of thrombolytic agents include streptokinase, urokinase, and tenecteplase (TNK), and tissue plasminogen activator (t-PA).

Antiarrhythmic Agents

Antiarrhythmic agents are used to treat disorders of the heart rate and rhythm. Examples of antiarrhythmic agents include amiodarone, dronedarone, quinidine, procainamide, lidocaine, and propafenone. Cardiac glycosides and beta blockers are also used as antiarrhythmic agents.

Combinations with amiodarone and dronedarone are of particular interest given the recently discovered synergistic effects of the sodium channel blocker ranolazine and amioarone and dronedarone.

Antihypertensive Agents

Antihypertensive agents are used to treat hypertension, a condition in which the blood pressure is consistently higher than normal. Hypertension is associated with many aspects of cardiovascular disease, including congestive heart failure, atherosclerosis, and clot for illation. Examples of antihypertensive agents include alpha-1-adrenergic antagonists, such as prazosin (Minipress), doxazosin mesylate (Cardura), prazosin hydrochloride (Minipress), prazosin, polythiazide (Minizide), and terazosin hydrochloride (Hytrin); beta-adrenergic antagonists, such as propranolol (Inderal), nadolol (Corgard), timolol (Blocadren), metoprolol (Lopressor), and pindolol (Visken); central alpha-adrenoceptor agonists, such as clonidine hydrochloride (Catapres), clonidine hydrochloride and chlorthalidone (Clorpres, Combipres), guanabenz Acetate (Wytensin), guanfacine hydrochloride (Tenex), methyldopa (Aldomet), methyldopa and chlorothiazide (Aldoclor), methyldopa and hydrochlorothiazide (Aldoril); combined alpha/beta-adrenergic antagonists, such as labetalol (Normodyne, Trandate), Carvedilol (Coreg); adrenergic neuron blocking agents, such as guanethidine (ismelin), reserpine (Serpasil); central nervous system-acting antihypertensives, such as clonidine (Catapres), methyldopa (Aldomet), guanabenz (Wytensin); anti-angiotensin II agents; ACE inhibitors, such as perindopril (Aceon) captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestril); angiotensin-II receptor antagonists, such as Candesartan (Atacand), Eprosartan (Teveten), Irbesartan (Avapro), Losartan (Cozaar), Telmisartan (Micardis), Valsartan (Diovan); calcium channel blockers, such as verapamil (Calan, Isoptin), diltiazem (Cardizem), nifedipine (Adalat, Procardia); diuretics; direct vasodilators, such as nitroprusside (Nipride), diazoxide (Hyperstat IV), hydralazine (Apresoline), minoxidil (Loniten), verapamil; and potassium channel activators, such as aprikalim, bimakalim, cromakalim, emakalim, nicorandil, and pinacidil.

Lipid Lowering Agents

Lipid lowering agents are used to lower the amounts of cholesterol or fatty sugars present in the blood. Examples of lipid lowering agents include bezafibrate (Bezalip), ciprofibrate (Modalim), and statins, such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), mevastatin, pitavastatin (Livalo, Pitava) pravastatin (Lipostat), rosuvastatin (Crestor), and simvastatin (Zocor).

In this invention, the patient presenting with an acute coronary disease event often suffers from secondary medical conditions such as one or more of a metabolic disorder, a pulmonary disorder, a peripheral vascular disorder, or a gastrointestinal disorder. Such patients can benefit from treatment of a combination therapy comprising administering to the patient ranolazine in combination with at least one therapeutic agent.

Pulmonary Disorders Combination Therapy

Pulmonary disorder refers to any disease or condition related to the lungs. Examples of pulmonary disorders include, without limitation, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, and emphysema.

Examples of therapeutics agents used to treat pulmonary disorders include bronchodilators including beta2 agonists and anticholinergics, corticosteroids, and electrolyte supplements. Specific examples of therapeutic agents used to treat pulmonary disorders include epinephrine, terbutaline (Brethaire, Bricanyl), albuterol (Proventil), salmeterol (Serevent, Serevent Diskus), theophylline, ipratropium bromide (Atrovent), tiotropium (Spiriva), methylprednisolone (Solu-Medrol, Medrol), magnesium, and potassium.

Metabolic Disorders Combination Therapy

Examples of metabolic disorders include, without limitation, diabetes, including type I and type II diabetes, metabolic syndrome, dyslipidemia, obesity, glucose intolerance, hypertension, elevated serum cholesterol, and elevated triglycerides.

Examples of therapeutic agents used to treat metabolic disorders include antihypertensive agents and lipid lowering agents, as described in the section “Cardiovascular Agent Combination Therapy” above. Additional therapeutic agents used to treat metabolic disorders include insulin, sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretin mimetics.

Peripheral Vascular Disorders Combination Therapy

Peripheral vascular disorders are disorders related to the blood vessels (arteries and veins) located outside the heart and brain, including, for example peripheral arterial disease (PAD), a condition that develops when the arteries that supply blood to the internal organs, arms, and legs become completely or partially blocked as a result of atherosclerosis.

Gastrointestinal Disorders Combination Therapy Gastrointestinal disorders refer to diseases and conditions associated with the gastrointestinal tract. Examples of gastrointestinal disorders include gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD), gastroenteritis, gastritis and peptic ulcer disease, and pancreatitis.

Examples of therapeutic agents used to treat gastrointestinal disorders include proton pump inhibitors, such as pantoprazole (Protonix), lansoprazole (Prevacid), esomeprazole (Nexium), omeprazole (Prilosec), rabeprazole; H2 blockers, such as cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), nizatidine (Axid); prostaglandins, such as misoprostoL (Cytotec); sucralfate; and antacids.

Antibiotics, Analgesics, Antidepressants and Anti-anxiety Agents Combination Therapy

Patients presenting with an acute coronary disease event may exhibit conditions that benefit from administration of therapeutic agent or agents that are antibiotics, analgesics, antidepressant and anti-anxiety agents in combination with ranolazine.

Antibiotics

Antibiotics are therapeutic agents that kill, or stop the growth of, microorganisms, including both bacteria and fungi. Example of antibiotic agents include.beta.-Lactam antibiotics, including penicillins (amoxicillin), cephalosporins, such as cefazolin, cefuroxime, cefadroxil (Duricef), cephalexin (Keflex), cephradine (Velosef), cefaclor (Ceclor), cefuroxime axtel (Ceftin), cefprozil (Cefzil), loracarbef (Lorabid), cefixime (Suprax), cefpodoxime proxetil (Vantin), ceftibuten (Cedax), cefdinir (Omnicef), ceftriaxone (Rocephin), carbapenems, and monobactams; tetracyclines, such as tetracycline; macrolide antibiotics, such as erythromycin; aminoglycosides, such as gentamicin, tobramycin, amikacin; quinolones such as ciprofloxacin; cyclic peptides, such as vancomycin, streptogramins, polymyxins; lincosamides, such as clindamycin; oxazolidinoes, such as linezolid; and sulfa antibiotics, such as sulfisoxazole.

Analgesics

Analgesics are therapeutic agents that are used to relieve pain. Examples of analgesics include opiates and morphinomimetics, such as fentanyl and morphine; paracetamol; NSAIDs, and COX-2 inhibitors. Given the ability of the sodium channel blockers of the invention to treat neuropathic pain via inhibition of the Nav 1.7 and 1.8 sodium channels, combination with analgesics are particularly envisioned. See U.S. Patent Application Publication 20090203707.

Antidepressant and Anti-anxiety Agents

Antidepressant and anti-anxiety agents include those agents used to treat anxiety disorders, depression, and those used as sedatives and tranquillizers. Examples of antidepressant and anti-anxiety agents include benzodiazepines, such as diazepam, lorazepam, and midazolam; benzodiazepines; barbiturates; glutethimide; chloral hydrate; meprobamate; sertraline (Zoloft, Lustral, Apo-Sertral, Asentra, Gladem, Serlift, Stimuloton); escitalopram (Lexapro, Cipralex); fluoxetine (Prozac, Sarafem, Fluctin, Fontex, Prodep, Fludep, Lovan); venlafaxine (Effexor XR, Efexor); citalopram (Celexa, Cipramil, Talohexane); paroxetine (Paxil, Seroxat, Aropax); trazodone (Desyrel); amitriptyline (Elavil); and bupropion (Wellbutrin, Zyban). Antidepressant and anti-anxiety agents may include neuroactive steroid and ketamine and related NMDA receptor antagonists.

Accordingly, one aspect of the invention provides for a composition comprising the sodium channel blockers of the invention and at least one therapeutic agent. In an alternative embodiment, the composition comprises the sodium channel blockers of the invention and at least two therapeutic agents. In further alternative embodiments, the composition comprises the sodium channel blockers of the invention and at least three therapeutic agents, the sodium channel blockers of the invention and at least four therapeutic agents, or the sodium channel blockers of the invention and at least five therapeutic agents.

The methods of combination therapy include co-administration of a single formulation containing the sodium channel blockers of the invention and therapeutic agent or agents, essentially contemporaneous administration of more than one formulation comprising the sodium channel blocker of the invention and therapeutic agent or agents, and consecutive administration of a sodium channel blocker of the invention and therapeutic agent or agents, in any order, wherein preferably there is a time period where the sodium channel blocker of the invention and therapeutic agent or agents simultaneously exert their therapeutic effect.

EXEMPLIFICATION

The representative examples that follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention.

The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimal reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.

Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, trituration, high pressure liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). Note that flash chromatography may either be performed manually or via an automated system. The compounds provided herein may be characterized by known standard procedures, such as nuclear magnetic resonance spectroscopy (NMR) or liquid chromatography mass spectrometry (LCMS). NMR chemical shifts are reported in part per million (ppm) and are generated using methods well known to those of skill in the art.

Exemplary general methods for analytical LCMS include Method A (Xtimate C₁₈ (2.1 mm×30 mm, 3 μm); A=H₂O (0.04% TFA) and B=CH₃CN (0.02% TFA); 50° C.; 1.2 mL/min; 10-80% B over 0.9 minutes, then 80% B for 0.6 minutes) and Method B (Chromolith Flash RP-18 endcapped C₁₈ (2 mm×25 mm); A=H₂O (0.04% TFA) and B=CH₃CN (0.02% TFA); 50° C.; 1.5 mL/min; 5-95% B over 0.7 minutes, then 95% B for 0.4 minutes)

LIST OF ABBREVIATIONS

-   -   Pd(dppf)Cl₂ [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)         dichloride     -   PdCl₂(PPh₃)₂ bis(triphenylphosphine)palladium(II) dichloride     -   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)     -   PyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphonium         hexafluorophosphate     -   DMF N,N-dimethylformamide     -   MeOH methanol     -   EtOH ethanol     -   THF tetrahydrofuran     -   EtOAc ethyl acetate     -   PE petroleum ether     -   MeCN or ACN acetonitrile     -   DMF N,N-dimethylformamide     -   DCM dichloromethane     -   EtOAc ethyl acetate     -   DMSO dimethyl sulfoxide     -   TFA trifluoroacetic acid     -   DIPEA N,N-diisopropylethylamine     -   DEA diethanolamine     -   KOAc potassium acetate     -   TsOH p-toluenesulfonic acid     -   n-BuLi n-butyllithium     -   KOAc potassium acetate     -   TBAB tetrabutylammonium bromide     -   MeMgBr methyl magnesium bromide     -   PCy3 tricyclohexylphosphine     -   XPhos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

Example I-1. Syntheses of Compound I-1: 6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-3-[(1R)-1-methoxyethyl]-[1,2,4]triazolo[4,3-a]pyrazine & Compound I-2: 6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-3-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[4,3-a]pyrazine. Note stereochemistry is randomly assigned

I-A2: 5-bromo-3-fluoro-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine

To a solution of 1,1,1-trifluoro-2-methyl-propan-2-ol (5.08 g, 39.69 mmol) in THF (50 mL) was added NaH (1.59 g, 39.69 mmol, 60% in oil) in portions at 0° C. The mixture was stirred at 25° C. for 30 mins. Then, 5-bromo-2,3-difluoro-pyridine (7 g, 36.09 mmol) was added and the mixture was stirred at 50° C. for 16 hours and at 80° C. for 4 hours. After cooling to 25° C., the mixture was quenched with H₂O (100 mL). The aqueous layer was extracted with EtOAc (150 mL×2). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give a crude product.

The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 15%) to give the product (6.3 g, 20.86 mmol, 57% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=7.99 (d, 1H), 7.54 (dd, 1H), 1.80 (s, 6H). LCMS Rt=0.98 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₉H9BrF₄NO [M+H]⁺304, found 303.7.

I-A3: 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine

A mixture of 5-bromo-3-fluoro-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (6.3 g, 20.86 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.83 g, 22.94 mmol), Pd(dppf)Cl₂ (1.53 g, 2.09 mmol) and KOAc (4.09 g, 41.71 mmol) in 1,4-dioxane (100 mL) was stirred at 90° C. for 2.5 hours. After cooling to 25° C., the suspension was diluted with EtOAc (50 mL), filtered through silica gel and eluted with EtOAc (50 mL). The combined filtrates were concentrated to give a crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10%) to give the product (5.7 g, 16.33 mmol, 78% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.26 (s, 1H), 7.67 (d, 1H), 1.83 (s, 6H), 1.34 (s, 12H). LCMS Rt=1.06 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₅H₂₁BF₄NO₃ [M+H]⁺350.1, found 350.0.

I-A4: 2-chloro-5-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]pyrazine

A mixture of Pd(dppf)Cl₂ (0.6 g, 0.82 mmol), Cs₂CO₃ (10.64 g, 32.65 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (5.7 g, 16.33 mmol) and 2-bromo-5-chloro-pyrazine (3.47 g, 17.96 mmol) in 1,4-dioxane (60 mL) and water (6 mL) under N₂ was stirred at 25° C. for 1.5 hours. Water (150 mL) was added and the aqueous layer was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 2% to 5%) to give the product (4.6 g, 13.70 mmol, 83% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.77 (s, 1H), 8.64 (s, 1H), 8.53 (d, 1H), 8.05 (dd, 1H), 1.88 (s, 6H). LCMS Rt=1.00 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₃H₁₁C₁F₄N₃₀ [M+H]⁺336.0, found 335.8.

I-A5: [5-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]pyrazin-2-yl]hydrazine

To a solution of 2-chloro-5-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]pyrazine (4.6 g, 13.70 mmol) in MeCN (50 mL) was added N₂H4·H₂O (3.43 g, 68.52 mmol) at 25° C. The mixture was stirred at 100° C. for 16 hours. After cooling to 25° C., the reaction was poured into water (150 mL). The mixture was extracted with EtOAc (30 mL×2). The combined organic layers was washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was triturated from EtOAc/PE=1/5 (60 mL) to give the product (3.8 g, 11.47 mmol, 83% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.43-8.41 (m, 2H), 8.29 (s, 1H), 7.94 (dd, 1H), 6.09 (brs, 1H), 3.92 (brs, 2H), 1.84 (s, 6H). LCMS Rt=0.78 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₃H₁₄F₄N₅0 [M+H]⁺332.1, found 331.9.

I-A7: 6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-3-(1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine

To a solution of 2-methoxypropanoic acid (190 mg, 1.83 mmol) in toluene (5 mL) was added (COCI)₂ (0.19 mL, 2.19 mmol) and 1 drop of DMF. The mixture was stirred at 28° C. for 1 hour. A solution of [5-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]pyrazin-2-yl]hydrazine (500 mg, 1.51 mmol) in toluene (2 mL) was added to the mixture. The mixture was stirred at 28° C. for 2 hours. To the above mixture was added TsOH (77.36 mg, 0.45 mmol). The mixture was stirred at 110° C. for 12 hours. After cooling to room temperature, H₂O (30 mL) was added. The mixture was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 40% to 70%) to give the product (60 mg, 0.15 mmol) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.42 (s, 1H), 8.59 (s, 1H), 8.49 (d, 1H), 8.01 (d, 1H), 5.23 (q, 1H), 3.38 (s, 3H), 1.88 (s, 6H), 1.79 (d, 3H). LCMS Rt=0.89 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₇H₁₈F₄N₅O₂[M+H]⁺400.1, found 400.1.

Compounds I-1 and1I-2: 6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-3-[(1R)-1-methoxyethyl]-[1,2,4]triazolo[4,3-a]pyrazine & 6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-3-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[4,3-a]pyrazine

6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-3-(1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (60 mg, 0.15 mmol) was purified by prep-HPLC [YMC Triart C₁₈ (150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 47-77% B over 9.5 minutes] to give the product (50 mg, 0.13 mmol) as a solid. Analysis SFC: (Chiralcel OJ-3 100×4.6 mm I.D., 3 μm. Mobile phase: A: CO₂, B: ethanol (0.05% DEA). Gradient: from 5% to 40% of B in 4 min and hold 40% for 2.5 min, then 5% of B for 1.5 min. Flow rate: 2.8 mL/min. Column temperature: 35° C. ABPR: 1500 psi) showed two peaks at 1.35 min (50%) and 1.42 min (50%). The stereochemistry of the compounds was randomly assigned.

6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-3-(1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (50 mg, 0.13 mmol) was purified by SFC (DAICEL CHIRALCEL OJ-H (250 mm×30 mm, 5 μm); A: CO₂, B=0.1% NH₃H₂O EtOH; 38° C.; 60 mL/min; 10% B; 11 min run; 40 injections) to give the Enantiomer 1, randomly assigned as 6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-3-[(1R)-1-methoxyethyl]-[1,2,4]triazolo[4,3-a]pyrazine (6.17 mg, 15.2 μmol, 12% yield) (Rt of Peak 1=1.35 min) as a solid and 6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-3-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[4,3-a]pyrazine (20 mg, 58.9 μmol) as a solid. 6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-3-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[4,3-a]pyrazine (20 mg, 58.9 μmol) was further purified by SFC (DAICEL CHIRALPAK IG (250 mm×30 mm, 10 μm); A: CO₂, B=0.1% NH₃H₂O MeOH; 38° C.; 60 mL/min; 15% B; 15 min run; 8 injections) to give Enantiomer 2, randomly assigned as 6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-3-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[4,3-a]pyrazine (13.4 mg, 33.6 μmol, 27% yield) (Rt of Peak 1=2.20 min) as a solid.

Compound I-1:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.42 (s, 1H), 8.59 (s, 1H), 8.49 (d, 1H), 8.00 (dd, 1H), 5.23 (q, 1H), 3.37 (s, 3H), 1.88 (s, 6H), 1.79 (d, 3H). LCMS Rt=1.20 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₇H₁₈ F₄N₅O₂ [M+H]⁺400.1, found 400.1.

Compound I-2:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.42 (s, 1H), 8.59 (s, 1H), 8.49 (d, 1H), 8.00 (dd, 1H), 5.23 (q, 1H), 3.37 (s, 3H), 1.88 (s, 6H), 1.79 (d, 3H). LCMS Rt=1.18 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₇H₁₈ F₄N₅O₂ [M+H]⁺400.1, found 400.1.

Example I-2. Syntheses of Compound I-3 & Compound I-4: (R)-6-(5-fluoro-6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-3-(1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine & (S)-6-(5-fluoro-6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-3-(1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine. Note stereochemistry is randomly assigned

I-A9: N′-(5-(5-fluoro-6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)pyrazin-2-yl)-2-methoxypropanehydrazide

To a mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl)cyclobutoxy]pyridine (500 mg, 1.38 mmol) and N′-(5-chloropyrazin-2-yl)-2-methoxy-propanehydrazide (351.27 mg, 1.52 mmol) and Cs₂CO₃ (902.14 mg, 2.77 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added Pd(dppf)Cl₂ (101.3 mg, 0.14 mmol) under N₂. The mixture was stirred at 90° C. for 16 hours. The mixture was filtered, and the filtrate was concentrated to remove dioxane. The aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to afford the product (594 mg, 1.38 mmol, 99% yield) as an oil. LCMS Rt=0.89 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₈ H₂₀F₄N₅O₃[M+H]⁺430.1, found 430.0.

I-A10: 6-(5-fluoro-6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-3-(1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine

To a mixture of N′-[5-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]pyrazin-2-yl]-2-methoxy-propanehydrazide (594 mg, 1.38 mmol) in DCM (20 mL) was added 2-methoxypyridine (1.21 g, 11.07 mmol) and Tf₂O (0.93 mL, 5.53 mmol). The mixture was stirred at 20° C. for 2 hours, quenched by adding water (50 mL), and extracted with EtOAc (50 mL×2). The combined organic phase was washed with saturated NaHCO₃ aqueous solution (30 mL), brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give the crude product. The residue was purified by flash chromatography (0 to 50% of EtOAc in PE) to give 6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-3-(1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (130 mg) as a solid. ¹H NMR (400 MHz, CDCl₃)^(6H)=9.41 (d, 1H), 8.59 (d, 1H), 8.46 (d, 1H), 8.07-7.99 (m, 1H), 5.26-5.15 (m, 1H), 3.36 (s, 3H), 3.02-2.83 (m, 2H), 2.81-2.67 (m, 3H), 2.09-1.91 (m, 3H), 1.77 (d, 3H).

Compounds 1-3 and1I-4: (S)-6-(5-fluoro-6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-3-(1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine & (R)-6-(5-fluoro-6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-3-(1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine

The mixture of 6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-3-(1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (160 mg, 0.39 mmol) was purified by SFC (DAICEL CHIRALCEL OJ-H (250 mm×30 mm, 5 μm); A: CO₂ and B=EtOH 0.1% NH₃·H₂O, 10% B); to give 6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-3-[(1R)-1-methoxyethyl]-[1,2,4]triazolo[4,3-a]pyrazine (32.34 mg) (Rt of Peak 1=3.004 mins) as a solid, and 6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-3-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[4,3-a]pyrazine (36.04 mg) (Rt of Peak 2=3.145 mins) as a solid.

Compound I-3:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.40 (d, 1H), 8.59 (d, 1H), 8.46 (d, 1H), 8.02 (dd, 1H), 5.21 (q, 1H), 3.36 (s, 3H), 2.99-2.82 (m, 2H), 2.81-2.67 (m, 2H), 2.11-1.87 (m, 2H), 1.77 (d, 3H). LCMS Rt=1.57 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₈ H₁₈F₄N₅O₂ [M+H]⁺412.1, found 412.2. Compound I-4:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.41 (d, 1H), 8.59 (d, 1H), 8.46 (d, 1H), 8.03 (dd, 10.4 Hz, 1H), 5.21 (q, 1H), 3.36 (s, 3H), 2.97-2.83 (m, 2H), 2.81-2.69 (m, 2H), 2.11-1.90 (m, 2H), 1.77 (d, 3H). LCMS Rt=1.57 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₈ H₁₈F₄N₅O₂ [M+H]⁺412.1, found 412.3.

Example I-3. Syntheses of Compound I-5 & Compound I-6: (S)-3-(1-methoxyethyl)-6-(6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine & (R)-3-(1-methoxyethyl)-6-(6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine. Note stereochemistry is randomly assigned

I-A12 N(-chloropyrazin-2-yl)-2-methoxypropanehydrazide

To a solution of (5-chloropyrazin-2-yl)hydrazine (10 g, 69.2 mmol) in THF (100 mL) was added 2-methoxypropanoyl chloride (10.4 g, 76.1 mmol) at 0° C. The mixture was stirred at 25° C. for 1 hour. To the mixture was added water (100 mL), and the mixture was extracted with EtOAc (100 mL×2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give the crude product (10 g, 28.6 mmol, 41% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.63 (s, 1H), 8.19-8.01 (m, 1H), 7.94-7.80 (m, 1H), 7.70-7.35 (m, 1H), 3.98-3.89 (m, 1H), 3.48-3.45 (m, 3H), 1.49-1.38 (m, 3H).

I-A14: 6-chloro-3-(1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine

To a mixture of N′-(5-chloropyrazin-2-yl)-2-methoxy-propanehydrazide (3.g, 13.0 mmol) in DCM (30 mL) was added 2-methoxypyridine (7.1 g, 65.0 mmol) and Tf₂O (5.49 mL, 32.5 mmol), and the mixture was stirred at 20° C. for 1 hour. To the mixture was added water (30 mL), and the aqueous phase was extracted with EtOAc (50 mL×2). The combined organic phase was washed with saturated NaHCO₃ aqueous solution (30 mL), brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give the crude product (1.2 g, 3.95 mmol) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.20-9.14 (m, 1H), 8.57-8.31 (m, 1H), 5.22-5.09 (m, 1H), 3.34 (s, 3H), 1.77-1.70 (m, 3H).

I-A15: 3-(1-methoxyethyl)-6-(6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

To a mixture of 6-chloro-3-(1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (300 mg, 1.41 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl) cyclobutoxy]pyridine (532.5 mg, 1.55 mmol) and Cs₂CO₃ (919.3 mg, 2.82 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was added Pd(dppf)Cl₂ (103.2 mg, 0.14 mmol) under N₂. The mixture was stirred at 90° C. for 2 hours. The mixture was filtered, and the filtrate was concentrated to remove dioxane. The aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give 3-(1-methoxyethyl)-6-(6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (300 mg, 0.61 mmol, 43% yield) ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.47-9.37 (m, 1H), 8.59-8.52 (m, 1H), 8.25-8.17 (m, 1H), 6.97-6.87 (m, 1H), 5.26-5.15 (m, 1H), 3.35 (s, 3H), 2.98-2.84 (m, 2H), 2.77-2.62 (m, 2H), 2.0-1.87 (m, 3H), 1.82-1.72 (m, 3H).

Compounds I-5 & I-6: (S)-3-(1-methoxyethyl)-6-(6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine & (R)-3-(1-methoxyethyl)-6-(6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

The mixture of 3-(1-methoxyethyl)-6-(6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.25 mmol) was purified by SFC (DAICEL CHIRALCEL OJ-H (250 mm×30 mm, 5 μm), A: CO₂ and B=MeOH 0.1% NH₃·H₂O, 10% B; to give (S)-3-(1-methoxyethyl)-6-(6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (49.2 mg, 0.13 mmol) as a solid and (R)-3-(1-methoxyethyl)-6-(6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (55.0 mg, 0.14 mmol) as a solid.

Compound I-5:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.42 (d, 1H), 8.70 (d, 1H), 8.56 (d, 1H), 8.20 (dd, 1H), 6.92 (d, 1H), 5.21 (d, 1H), 3.36 (s, 3H), 2.98-2.85 (m, 2H), 2.77-2.65 (m, 2H), 2.08-1.89 (m, 2H), 1.77 (d, 3H). LCMS Rt=1.544 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₈ H₁₉F₃N₅O₂[M+H] 394.2, found 394.2. Compound I-6:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.42 (d, 1H), 8.70 (d, 1H), 8.56 (d, 1H), 8.21 (dd, 1H), 6.92 (d, 1H), 5.21 (d, 1H), 3.36 (s, 3H), 2.92 (br d, 2H), 2.76-2.66 (m, 2H), 2.07-1.90 (m, 2H), 1.77 (d, 3H). LCMS Rt=1.539 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₈ H₁₉F₃N₅O₂[M+H] 394.2, found 394.2.

Example I-4. Synthesis of Compound I-7: (S)-3-(1-ethoxyethyl)-6-(5-fluoro-6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

I-A17: (S)-2-ethoxy-N′-(5-(5-fluoro-6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)pyrazin-2-yl)propanehydrazide

To a mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl)cyclobutoxy]pyridine (400 mg, 1.11 mmol) and (S)—N′-(5-chloropyrazin-2-yl)-2-ethoxypropanehydrazide (298.1 mg, 1.22 mmol) and Cs₂CO₃ (721.7 mg, 2.22 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added Pd(dppf)Cl₂ (81.0 mg, 0.11 mmol) under N₂. After stirring at 90° C. for 16 hours, the mixture was filtered, and the filtrate was concentrated to remove dioxane. The aqueous layer was extracted with EtOAc (30 mL×2).

The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to afford the product (500 mg, crude) as an oil. LCMS Rt=0.92 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₉H₂₂F₄N₅O₃[M+H]⁺444.2, found 444.0.

I-A18: (S)-3-(1-ethoxyethyl)-6-(5-fluoro-6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

To a mixture of (S)-2-ethoxy-N′-(5-(5-fluoro-6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)pyrazin-2-yl)propanehydrazide (500 mg, crude) in DCM (20 mL) was added 2-methoxypyridine (513.1 mg, 4.70 mmol) and Tf₂O (0.40 mL, 2.35 mmol), and the mixture was stirred at 20° C. for 2 hours. The mixture was diluted with water (20 mL), and the aqueous phase was extracted with EtOAc (20 mL×2). The combined organic phase was washed with saturated NaHCO₃ aqueous solution (15 mL), brine (15 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography (0 to 30% of EtOAc in PE) to give the product (200 mg, 0.49 mmol, 42% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.40 (d, 1H), 8.65 (d, 1H), 8.44 (d, 1H), 8.02 (dd, 1H), 5.36-5.25 (m, 1H), 3.68-3.53 (m, 1H), 3.47-3.32 (m, 1H), 2.98-2.85 (m, 2H), 2.82-2.70 (m, 2H), 2.03-1.91 (m, 2H), 1.76 (d, 3H), 1.25-1.22 (m, 3H).

Compound I-7: (S)-3-(1-ethoxyethyl)-6-(5-fluoro-6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

The mixture of (S)-3-(1-ethoxyethyl)-6-(5-fluoro-6-(1-(trifluoromethyl) cyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (200 mg, 0.47 mmol) was purified by SFC (DAICEL CHIRALCEL OJ-H (250 mm×30 mm, 5 μm); A: CO₂, B=EtOH 0.1% NH₃·H₂O; 10% B; 60 mL/min; to afford (S)-3-(1-ethoxyethyl)-6-(5-fluoro-6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo [4,3-a]pyrazine (87.9 mg, 0.21 mmol) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.40 (d, 1H), 8.65 (d, 1H), 8.44 (d, 1H), 8.02 (dd, 1H), 5.31 (q, 1H), 3.66-3.53 (m, 1H), 3.47-3.35 (m, 1H), 2.98-2.86 (m, 2H), 2.81-2.70 (m, 2H), 2.09-1.90 (m, 2H), 1.76 (d, 3H), 1.24 (t, 3H). LCMS Rt=1.63 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₉H₂₀F₄N₅O₂[M+H]⁺426.1, found 426.3.

Example I-5. Synthesis of Compound I-8: (S)-3-(1-ethoxyethyl)-6-(6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

I-A21: (S)-6-chloro-3-(1-ethoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine To a mixture of (S)—N′-(5-chloropyrazin-2-yl)-2-ethoxypropanehydrazide (1 g, 4.09 mmol) in DCM (10 mL) was added 2-methoxypyridine (2.23 g, 20.4 mmol) and Tf₂0 (1.73 mL, 10.2 mmol). The mixture was stirred at 20° C. for 2 hours. To the mixture was added water (50 mL), and the aqueous phase was extracted with EtOAc (50 mL×2). The combined organic phase was washed with saturated NaHCO₃ aqueous solution (30 mL), brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give the crude product of 6-chloro-3-(1-ethoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (500 mg, 1.54 mmol, 38% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.25-9.10 (m, 1H), 8.59-8.37 (m, 1H), 5.33-5.18 (m, 1H), 3.68-3.51 (m, 1H), 3.44-3.23 (m, 1H), 1.76-1.69 (m, 3H), 1.25-1.20 (m, 3H). Compound I-8: (S)-3-(1-ethoxyethyl)-6-(6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

To a mixture of (S)-6-chloro-3-(1-ethoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (400 mg, 1.76 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (666.13 mg, 2.01 mmol) and Cs₂CO₃ (1149.92 mg, 3.53 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was added Pd(dppf)Cl₂ (129.13 mg, 0.18 mmol) under N₂. The mixture was stirred at 90° C. for 2 hours. The mixture was filtered, and the filtrate was concentrated to remove dioxane. The aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The mixture of (300 mg, 0.76 mmol) was purified by SFC (DAICEL CHIRALPAK AD (250 mm×30 mm, 10 μm; A: CO₂ and B=EtOH 0.1% NH₃·H₂O; 10% B) to give the product (117.4 mg, 0.30 mmol, 39% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)^(6H)=9.41 (d, 1H), 8.68 (d, 1H), 8.61 (d, 1H), 8.15 (dd, 1H), 6.91 (d, 1H), 5.31 (d, 1H), 3.59 (br d, 1H), 3.48-3.35 (m, 1H), 1.86 (s, 6H), 1.77 (d, 3H), 1.24 (t, 3H). LCMS Rt=2.292 min in 3.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₈ H₂₁F₃N₅O₂[M+H]⁺395.16, found 396.2.

Example I-6. Syntheses of Compound I-9 and I-10: (R)-3-(1-methoxyethyl)-6-(6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine & (S)-3-(1-methoxyethyl)-6-(6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine. Note stereochemistry is randomly assigned

I-A23: 5-bromo-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine

To a solution of 1,1,1-trifluoro-2-methyl-propan-2-ol (5.46 g, 42.6 mmol) in THE (80 mL) was added NaH (1.7 g, 42.6 mmol) (60% in oil) in portions at 0° C. After stirring at 25° C. for 30 minutes, 5-bromo-2-fluoro-pyridine (5.0 g, 28.4 mmol) was added. After stirring at 80° C. for another 48 hours, the mixture was cooled to 25° C. and quenched with H₂O (100 mL). The aqueous layer was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography on silica pad (0 to 2% of EtOAc in PE) to give the product (4.2 g, 14.8 mmol, 52% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)^(6H)=8.17 (d, 1H), 7.66 (dd, 1H), 6.68 (d, 1H), 1.77 (d, 6H).

I-A20: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine

A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.63 g, 22.18 mmol), 5-bromo-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy) pyridine (4.2 g, 14.8 mmol), KOAc (2.9 g, 29.6 mmol) and Pd(dppf)Cl₂ (1.08 g, 1.48 mmol) in 1,4-dioxane (70 mL) was stirred at 80° C. for 16 hours under N₂ atmosphere. After cooling to 25° C., the reaction was concentrated and diluted with H₂O (100 mL), then extracted with EtOAc (50 mL×3). The combined organic phase was washed with brine (200 mL), dried over Na₂SO₄, filtered, and concentrated to give the crude product, which was purified with flash chromatography on silica gel (EtOAc in PE=0% to 2%) to give the product (3.2 g, 7.73 mmol, 52% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.51 (d, 1H), 7.94 (dd, 1H), 6.74 (dd, 1H), 1.82 (d, 6H), 1.34 (s, 12H).

Compound I-9 & I-10: (R)-3-(1-methoxyethyl)-6-(6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine & (S)-3-(1-methoxyethyl)-6-(6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

To a mixture of 6-chloro-3-(1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (300 mg, 1.41 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (513.9 mg, 1.55 mmol) and Cs₂CO₃ (919.3 mg, 2.82 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL) was added Pd(dppf)Cl₂ (103.2 mg, 0.14 mmol) under N₂. After stirring at 90° C. for 16 hours, the mixture was filtered and water (30 mL) was added. The aqueous layer was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography (0 to 50% of EtOAc in PE) to give the product (120 mg, 0.25 mmol) as a crude product, which was purified by SFC (DAICEL CHIRALPAK AD (250 mm×30 mm, 10 μm); A: CO₂ and B=EtOH 0.1% NH₃·H₂O; 20% B; 100% B; 60 mL/min; 80 injections) to afford (S)-3-(1-methoxyethyl)-6-(6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (15 mg, 0.04 mmol) as a solid and (R)-3-(1-methoxyethyl)-6-(6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (17.1 mg, 0.04 mmol) as a solid.

Compound I-9 ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.42 (d, 1H), 8.69 (d, 1H), 8.54 (d, 1H), 8.16 (dd, 1H), 6.91 (d, 1H), 5.22 (q, 1H), 3.36 (s, 3H), 1.85 (s, 6H), 1.77 (d, 3H). LCMS Rt=1.003 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₇H₁₉F₃N₅O₂[M+H]+ 382.2, found 382.2. Compound I-10 ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.42 (d, 1H), 8.70 (d, 1H), 8.55 (d, 1H), 8.16 (dd, 1H), 6.91 (d, 1H), 5.22 (q, 1H), 3.36 (s, 3H), 1.86 (s, 6H), 1.78 (d, 3H). LCMS Rt =0.994 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₇H₁₉F₃N₅O₂[M+H]+ 382.2, found 382.2.

Example I-7. Synthesis of Compound I-11: (S)-3-(1-ethoxyethyl)-6-(6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

I-A40b: (S)-2-ethoxypropanoate

To a solution of iodoethane (45.0 g, 288.2 mmol), Ag₂O (66.8 g, 288.2 mmol) in Et₂O (300 mL) under N₂, shielded from the light was added methyl (S)-(−)-lactate (13.8 mL, 144.1 mmol). The reaction mixture was stirred at 20° C. for 16 hours under N₂. Then the reaction mixture was filtered, and the filter cake was washed with DCM. The filtrate was concentrated to give methyl (S)-2-ethoxypropanoate (22 g, 164.8 mmol, 50% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=4.01-3.94 (m, 1H), 3.75 (s, 3H), 3.52-3.35 (m, 1H), 1.43-1.39 (m, 4H), 1.25-1.18 (m, 3H).

I-A40c: (S)-2-ethoxypropanoic acid

To a solution of methyl (2S)-2-ethoxypropanoate (22 g, 166.5 mmol) in THF/MeOH/H₂O (350 mL), was added LiOH·H₂O (39.9 g, 1664.7 mmol). After stirring at 20° C. for 4 hours, HCl (2 M) (500 mL) was added, and the aqueous phase was extracted with DCM (2×200 mL). The combined organic phase was concentrated to give (S)-2-ethoxypropanoic acid (19 g, 159.2 mmol, 96% yield) as an oil. ¹H NMR (400 MHz, CDCl₃) S_(H)=4.05-3.95 (m, 1H), 3.68-3.48 (m, 2H), 1.48-1.42 (m, 3H), 1.22-1.29 (m, 3H).

I-A40d: (S)-2-ethoxypropanoyl chloride

To a solution of 2-ethoxypropanoic acid (4.2 g, 35.6 mmol) in THE (80 mL) was added oxalyl chloride (5.42 g, 42.7 mmol) and DMF (1.0 mL, 35.6 mmol). The mixture was stirred at 25° C. for 1 hour. The solution was used for the next step directly without further purification.

I-A16: (S)—N′-(5-chloropyrazin-2-yl)-2-ethoxypropanehydrazide

To a solution of (S)-2-ethoxypropanoyl chloride (4.82 g, 35.3 mmol) in THF (80 mL) was added (5-chloropyrazin-2-yl)hydrazine (3.0 g, 20.8 mmol) at 0° C. After stirring at 25° C. for 1 hour, water (100 mL) was added to the mixture, and the aqueous phase was extracted with DCM (100 mL×2). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give the crude product (6.2 g) as a solid, which was triturated from (PE:EtOAc=6:1, 60 ml) at 25° C. to give to give N′-(5-chloropyrazin-2-yl)-2-ethoxy-propanehydrazide (3.3 g, 13.5 mmol, 53% yield) as a solid. 1H NMR (400 MHz, CDCl₃)δ_(H)=8.53 (s, 1H), 8.31-8.06 (m, 1H), 7.89 (s, 1H), 6.97 (br s, 1H), 4.04 (q, 1H), 3.80-3.47 (m, 2H), 1.45 (d, 3H), 1.32-1.23 (m, 3H).

I-A26: (S)-2-ethoxy-N′-(5-(6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)pyrazin-2-yl)propanehydrazide

To a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl) cyclobutoxy]pyridine (400 mg, 1.17 mmol) and N′-(5-chloropyrazin-2-yl)-2-ethoxy-propanehydrazide (313.7 mg, 1.28 mmol) and Cs₂CO₃ (759.6 mg, 2.33 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added Pd(dppf)Cl₂ (85.3 mg, 0.12 mmol) under N₂. After stirring at 90° C. for 16 hours, the mixture was filtered water (50 ml) was added. The aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to afford the product (1.0 g) as a solid, which was used for the next step directly without further purification.

Compound I-11: (S)-3-(1-ethoxyethyl)-6-(6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

To a mixture of (S)-2-ethoxy-N′-(5-(6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl) pyrazin-2-yl)propanehydrazide (1.0 g, 2.35 mmol) in DCM (15 mL) was added 2-methoxypyridine (0.54 g, 4.94 mmol) and Tf₂O (0.66 g, 2.35 mmol). After stirring at 20° C. for 16 hours, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL×2). The combined organic phase was washed with saturated NaHCO₃ aqueous solution (30 mL), brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography (0 to 40% of EtOAc in PE) to give crude product, which was purified by prep-HPLC (Phenomenex Gemini-NX 80×30 mm, 3 μm) Mobile phase: A: water (10 mM NH₄HCO₃), B: acetonitrile, Gradient: from 53% to 83% B in 9 min, then 100% of B for 1.5 min; 30 mL/min, to give (S)-3-(1-ethoxyethyl)-6-(6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (55 mg, 0.14 mmol) as impure product. The impure product (55 mg, 0.14 mmol) was further purified by SFC (DAICEL CHIRALPAK AD (250 mm×30 mm, 10 μm) A: CO₂ and B=EtOH 0.1% NH₃·H₂O; Gradient: from 20% B to 100% B; 60 mL/min; 70 injections); to give the product (34.4 mg, 0.08 mmol, 63% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.41 (d, 1H), 8.69 (d, 1H), 8.62 (d, 1H), 8.19 (dd, 1H), 6.92 (d, 1H), 5.31 (q, 1H), 3.70-3.51 (m, 1H), 3.48-3.32 (m, 1H), 2.98-2.86 (m, 2H), 2.76-2.65 (m, 2H), 2.10-1.90 (m, 2H), 1.76 (d, 3H), 1.24 (t, 3H). LCMS Rt=1.033 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₉H₂₁F₃N₅O₂[M+H]+ 408.3, found 408.3.

Example I-8. Synthesis of Compound I-12: 6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-3-[(1S)-1-ethoxyethyl]-[1,2,4]triazolo[4,3-a]pyrazine

I-A27: (S)-2-ethoxy-N′-(5-(5-fluoro-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)pyrazin-2-yl)propanehydrazide

To a mixture of (S)—N′-(5-chloropyrazin-2-yl)-2-ethoxypropanehydrazide (353.29 mg, 1.44 mmol) (353.3 mg, 1.44 mmol) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (500 mg, 1.43 mmol) and Cs₂CO₃ (933.2 mg, 2.86 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was added Pd(dppf)Cl₂ (104.8 mg, 0.14 mmol) under N₂. The mixture was stirred at 90° C. for 16 hours. The mixture was filtered, and the filtrate was concentrated to remove dioxane. The aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to afford the product (617.8 mg, 1.43 mmol, 100% yield) as a solid. LCMS Rt=0.944 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₈ H₂₂F₄N₅03 [M+H]⁺432.1, found 432.1.

I-A28: 3-(1-ethoxyethyl)-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

To a mixture of (S)-2-ethoxy-N′-(5-(5-fluoro-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)pyrazin-2-yl)propanehydrazide (600 mg, 1.39 mmol) in DCM (2 mL) was added 2-methoxypyridine (607.2 mg, 5.56 mmol) and Tf₂O (0.47 mL, 2.78 mmol). The mixture was stirred at 20° C. under N₂ for 2 hours, quenched with water (5 mL), extracted with DCM (5 mL×2), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (EtOAc in PE=30% to 50%) to afford the product (220 mg, 0.53 mmol, 38% yield) as a solid. LCMS Rt=0.946 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₈H₂₀F₄N₅O₂[M+H]⁺414.0, found 414.0.

Compound I-12:

(S)-3-(1-ethoxyethyl)-6-(5-fluoro-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

The residue of (S)-3-(1-ethoxyethyl)-6-(5-fluoro-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.24 mmol) was purified by SFC (DAICEL CHIRALCEL OD-H (250 mm×30 mm, 5 μm); A: CO₂ and B=EtOH 0.1% NH₃·H₂O; 25% B; 60 mL/min); to the product (13.1 mg, 0.03 mmol, 12% yield) as a solid and as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.40 (d, 1H), 8.65 (d, 1H), 8.46 (d, 1H), 8.03-7.95 (m, 1H), 5.36-5.27 (m, 1H), 3.66-3.56 (m, 1H), 3.47-3.35 (m, 1H), 1.87 (s, 6H), 1.77 (d, 3H), 1.25 (t, 3H) LCMS Rt=1.287 min in 2.0 min chromatography, 10-80AB, MS ESI calcd for C₁₈ H₂₀F₄N₅O₂[M+H] 414.1, found 414.1.

Example I-9. Synthesis of Compound I-13: (R)-3-(1-ethoxyethyl)-6-(5-fluoro-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

I-A30: (R)-3-[1-ethoxyethyl]-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

To a mixture of (R)-6-chloro-3-(1-ethoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (200 mg, 0.88 mmol) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (400.5 mg, 1.15 mmol) and Cs₂CO₃ (575.0 mg, 1.76 mmol) in 1,4-dioxane (5 mL) was added Pd(dppf)Cl₂ (83.9 mg, 0.11 mmol) under N₂. The mixture was stirred at 100° C. for 3 hours. After cooling, the mixture was filtered, and the filtrate was concentrated to remove dioxane. The aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (PE: EtOAc=1:1) to afford the product (200 mg, 0.48 mmol, 55% yield) as a solid. LCMS Rt=1.011 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₈H₂₀F₄N₅O₂[M+H]⁺414.0, found 414.0.

Compound1I-13: (R)-3-(1-ethoxyethyl)-6-(5-fluoro-6-((1,1,1-trifluoro-2-methylpropan-2-yl) oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

The residue was purified by SFC (DAICEL CHIRALCEL OD-H (250 mm×30 mm, 5 μm); A: CO₂ and B=EtOH 0.1% NH₃·H₂); 15% B; 60 mL/min; to afford the product (97.8 mg, 0.24 mmol, 49% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)^(6H)=9.41 (d, 1H), 8.65 (d, 1H), 8.46 (d, 1H), 8.03-7.94 (m, 1H), 5.37-5.25 (m, 1H), 3.65-3.56 (m, 1H), 3.46-3.37 (m, 1H), 1.87 (s, 6H), 1.77 (d, 3H), 1.25 (t, 3H) LCMS Rt=1.007 min in 1.5 min chromatography, 5-95AB, MS ESI calcd for C₁₈H₂₀F₄N₅O₂[M+H] 414.0, found 414.0.

Example I-10. Synthesis of Compound I-14: (R)-3-(1-ethoxyethyl)-6-(5-fluoro-6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

To a mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl)cyclobutoxy]pyridine (350.5 mg, 0.97 mmol) and 6-chloro-3-[(1R)-1-ethoxyethyl]-[1,2,4]triazolo[4,3-a]pyrazine (200 mg, 0.88 mmol) and Cs₂CO₃ (575.0 mg, 1.76 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added Pd(dppf)Cl₂ (64.6 mg, 0.09 mmol) under N₂. The mixture was stirred at 90° C. for 3 hours. The mixture was filtered, and the filtrate was concentrated to remove dioxane. The aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude was purified by flash column (0 to 30% to 50% of EtOAc in PE) to give the product (200 mg, 0.47 mmol, 53% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.40 (d, 1H), 8.65 (d, 1H), 8.44 (d, 1H), 8.02 (dd, 1H), 5.40-5.21 (m, 1H), 3.67-3.55 (m, 1H), 3.49-3.27 (m, 1H), 2.98-2.85 (m, 2H), 2.82-2.68 (m, 2H), 2.11-1.89 (m, 2H), 1.76 (d, 3H), 1.24 (t, 3H).

The above solid (200 mg) was purified by SFC (DAICEL CHIRALCEL OJ-H (250 mm×30 mm, 5 μm); A: CO₂ B=EtOH 0.1% NH₃·H₂O, 15% B; 60 mL/min); to give the product (124.0 mg, 0.29 mmol) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.40 (d, 1H), 8.65 (d, 1H), 8.44 (d, 1H), 8.02 (dd, 1H), 5.31 (q, 1H), 3.66-3.53 (m, 1H), 3.41 (qd, 1H), 2.99-2.84 (m, 2H), 2.81-2.69 (m, 2H), 2.12-1.92 (m, 2H), 1.76 (d, 3H), 1.24 (t, 3H). LCMS Rt=1.30 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₉H₂₀F₄N₅O₂[M+H]⁺426.1, found 426.1.

Example I-11. Syntheses of Compounds 1-15, 1-16,1-17 & I-18: 6-(6-((R)-1-cyclopropyl-2,2,2-trifluoroethoxy)-5-fluoropyridin-3-yl)-3-((R)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine & 6-(6-((R)-1-cyclopropyl-2,2,2-trifluoroethoxy)-5-fluoropyridin-3-yl)-3-((S)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine & 6-(6-((S)-1-cyclopropyl-2,2,2-trifluoroethoxy)-5-fluoropyridin-3-yl)-3-((R)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine & 6-(6-((S)-1-cyclopropyl-2,2,2-trifluoroethoxy)-5-fluoropyridin-3-yl)-3-((S)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine, Note stereochemistry is randomly assigned

I-A33: 5-bromo-2-(1-cyclopropyl-2, 2,2-trifluoroethoxy)-3-fluoropyridine

To a solution of NaH (342.6 mg, 8.57 mmol) in THF (10 mL) was added 1-cyclopropyl-2, 2,2-trifluoro-ethanol (1.20 g, 8.57 mmol) in portions at 0° C. After stirring at 0° C. for 1 hour, 5-bromo-2,3-difluoro-pyridine (1.66 g, 8.57 mmol) was added. The mixture was stirred at 25° C. for 16 hours. The mixture was quenched with H₂O (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography (0% of EtOAc in PE) to give the product (2.10 g, 6.02 mmol, 70% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=7.93 (d, 1H), 7.55 (dd, 8.8 Hz, 1H), 5.32-5.13 (m, 1H), 1.37-1.29 (m, 1H), 0.86 (br d, 1H), 0.80-0.73 (m, 1H), 0.62-0.55 (m, 2H).

I-A34: 2-(1-cyclopropyl-2, 2,2-trifluoroethoxy)-3-fluoro-5-(4,4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine

A mixture of 5-bromo-2-(1-cyclopropyl-2,2,2-trifluoro-ethoxy)-3-fluoro-pyridine (2.5 g, 7.96 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.03 g, 11.94 mmol), Pd(dppf)Cl₂ (582.4 mg, 0.80 mmol) and KOAc (1.56 g, 15.9 mmol) in 1,4-dioxane (15 mL) was stirred at 90° C. for 16 hours under N₂. The mixture was cooled to room temperature, filtered, and concentrated. The residue was purified by flash column chromatography (0 to 5% of EtOAc in PE) to give the product (3.70 g, 7.17 mmol, 90% yield,) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.20 (d, 1H), 7.69 (dd, 10.4 Hz, 1H), 5.47-5.33 (m, 1H), 1.33 (s, 12H), 1.26 (s, 2H), 0.78-0.71 (m, 1H), 0.64-0.59 (m, 2H).

I-A35: 6-(6-(1-cyclopropyl-2, 2, 2-trifluoroethoxy)-5-fluoropyridin-3-yl)-3-(1-methoxyethyl)-[1,2, 4] triazolo [4, 3-a] pyrazine

To a mixture of 2-(1-cyclopropyl-2,2,2-trifluoro-ethoxy)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (800 mg, 2.22 mmol) and 6-chloro-3-(1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (565.2 mg, 2.66 mmol) and Cs₂CO₃ (1443.4 mg, 4.43 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was added Pd(dppf)Cl₂ (162.1 mg, 0.22 mmol) under N₂. The mixture was stirred at 90° C. for 16 hours. The mixture was filtered, and the filtrate was concentrated to remove dioxane. The aqueous layer was extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography (50 to 70% of EtOAc in PE) to give 500 mg of impure product, which was further purified by pre-HPLC (Phenomenex Gemini-NX (80×30 mm, 3 μm; A=water (10 mM NH₄HCO₃), B=acetonitrile; Gradient: from 49% to 79% of B) to give 6-[6-(1-cyclopropyl-2,2,2-trifluoro-ethoxy)-5-fluoro-3-pyridyl]-3-(1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (400 mg, 0.68 mmol, 80% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.41 (d, 1H), 8.57 (d, 1H), 8.49-8.38 (m, 1H), 8.12-7.95 (m, 1H), 5.42-5.32 (m, 1H), 5.26-5.17 (m, 1H), 3.56 (s, 1H), 3.36 (s, 3H), 1.78 (d, 3H), 1.43-1.33 (m, 1H), 0.83-0.74 (m, 1H), 0.64-0.55 (m, 2H).

Compounds I-15, 1-16, 1-17 & I-18: 6-(6-((R)-1-cyclopropyl-2,2,2-trifluoroethoxy)-5-fluoropyridin-3-yl)-3-((R)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine & 6-(6-((R)-1-cyclopropyl-2,2,2-trifluoroethoxy)-5-fluoropyridin-3-yl)-3-((S)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine & 6-(6-((S)-1-cyclopropyl-2,2,2-trifluoroethoxy)-5-fluoropyridin-3-yl)-3-((R)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine & 6-(6-((S)-1-cyclopropyl-2,2,2-trifluoroethoxy)-5-fluoropyridin-3-yl)-3-((S)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine

6-[6-(1-cyclopropyl-2,2,2-trifluoro-ethoxy)-5-fluoro-3-pyridyl]-3-(1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (400 mg, 0.97 mmol) was purified by SFC (DAICALPAK AD (250 mm×30 mm, 10 μm); A: CO₂ and B=EtOH 0.1% NH₃·H₂O; 15% B) to give 6-(6-((S)-1-cyclopropyl-2,2,2-trifluoroethoxy)-5-fluoropyridin-3-yl)-3-((S)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (Rt of Peak 4=2.737 min) (80 mg) and a mixture of Peak 1, Peak 2 and Peak 3 (270 mg) both as an oil.

A mixture of Peak 1, Peak 2 and Peak 3 (270 mg, 0.66 mmol) was purified by SFC (DAICALPAK AD (250 mm×10 mm, 10 μm); A: CO₂ and B=MeOH 0.1% NH₃·H₂O; 20% B); to give 6-(6-((R)-1-cyclopropyl-2,2,2-trifluoroethoxy)-5-fluoropyridin-3-yl)-3-((R)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (Rt of Peak 1=2.551 min) (30 mg, 0.07 mmol, 10% yield) and a mixture of Peak 2 and Peak 3 (120 mg, 0.29 mmol) both as an oil.

A mixture of Peak 2 and Peak 3 (120 mg, 0.29 mmol) was purified by SFC (DAICALPAK AD (250 mm×30 mm, 10 μm); A: CO₂ and B=EtOH 0.1% NH₃·H₂O; 15% B); to give 6-(6-((R)-1-cyclopropyl-2,2,2-trifluoroethoxy)-5-fluoropyridin-3-yl)-3-((S)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (Rt of Peak 2=2.072 min) (50.0 mg, 0.12 mmol, 41.7% yield) and 6-(6-((S)-1-cyclopropyl-2,2,2-trifluoroethoxy)-5-fluoropyridin-3-yl)-3-((R)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (Rt of Peak 3=2.201 min) (50.0 mg, 0.12 mmol, 41.7% yield) both as an oil.

The above Peak 1 (30.0 mg, 0.07 mmol) was purified by prep-TLC (PE:EA=1:2) to give 6-(6-((R)-1-cyclopropyl-2,2,2-trifluoroethoxy)-5-fluoropyridin-3-yl)-3-((R)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (Peak 1, Rt=2.551 min, 3.16 mg) as an oil.

The above Peak 2 (40.0 mg, 0.10 mmol) was purified by prep-TLC (PE:EA=1:2) to give 6-(6-((R)-1-cyclopropyl-2,2,2-trifluoroethoxy)-5-fluoropyridin-3-yl)-3-((S)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (Peak 2, Rt=2.072 min, 15.1 mg) as an oil.

The above Peak 3 (40 mg, 0.10 mmol) was purified by prep-TLC (PE:EA=1:2) to give 6-(6-((S)-1-cyclopropyl-2,2,2-trifluoroethoxy)-5-fluoropyridin-3-yl)-3-((R)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (Peak 3, Rt=2.201 min, 26.82 mg) as an oil.

The above Peak 4 (40.0 mg, 0.10 mmol) was purified by prep-TLC (PE:EA=1:2) to give 6-(6-((S)-1-cyclopropyl-2,2,2-trifluoroethoxy)-5-fluoropyridin-3-yl)-3-((S)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (peak 4, Rt=2.737 min, 6.28 mg) as an oil.

Compound I-15:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.40 (d, 1H), 8.57 (d, 1H), 8.43 (d, 1H), 8.07-7.96 (m, 1H), 5.43-5.29 (m, 1H), 5.25-5.15 (m, 1H), 3.36 (s, 3H), 1.77 (d, 3H), 1.40-1.32 (m, 1H), 0.83-0.75 (m, 1H), 0.68-0.59 (m, 3H). MS ESI calcd. for C₁₈ H₁₈F₄N₅O₂ [M+H]+ 412.1 Compound I-16:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.41 (d, 1H), 8.57 (d, 1H), 8.43 (d, 1H), 8.05-7.98 (m, 1H), 5.42-5.34 (m, 1H), 5.25-5.19 (m, 1H), 3.36 (s, 3H), 1.78 (d, 3H), 1.42-1.34 (m, 1H), 0.83-0.76 (m, 1H), 0.68-0.61 (m, 3H). MS ESI calcd. for C₁₈ H₁₈F₄N₅O₂ [M+H]+ 412.1 Compound I-17:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.41 (d, 1H), 8.57 (d, 1H), 8.43 (d, 1H), 8.07-6.98 (m, 1H), 5.43-5.33 (m, 1H), 5.25-5.17 (m, 1H), 3.36 (s, 3H), 1.77 (d, 3H), 1.41-1.32 (m, 1H), 0.83-0.75 (m, 1H), 0.69-0.61 (m, 3H).0 MS ESI calcd. for C₁₈ H₁₈F₄N₅O₂ [M+H]+ 412.1 Compound I-18:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.41 (s, 1H), 8.57 (s, 1H), 8.43 (br s, 1H), 8.02 (br d, 1H), 5.41-5.34 (m, 1H), 5.25-5.18 (m, 1H), 3.36 (s, 3H), 1.77 (br d, 3H), 1.42-1.32 (m, 1H), 0.83-0.75 (m, 1H), 0.68-0.58 (m, 3H). MS ESI calcd. for C₁₈ H₁₈F₄N₅O₂ [M+H]+ 412.1, found 412.1

Example I-12. Synthesis of Compound I-19: (R)-3-(1-ethoxyethyl)-6-(6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

I-A41b: (R)-2-ethoxypropanoate

To a solution of Ag₂0 (178.1 g, 768.5 mmol), methyl (2R)-2-hydroxypropanoate (40 g, 384.3 mmol) in ether (600 mL) under N₂, shielded from the light, was added iodoethane (62.1 mL, 768.5 mmol). After stirring at 20° C. for 12 hours under N₂, the reaction mixture was filtered, and the filter cake was washed with DCM (50 mL). The filtrate was concentrated to give methyl (R)-2-ethoxypropanoate (70 g, 524.4 mmol, crude) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=4.40-4.24 (m, 3H), 3.86-3.71 (m, 3H), 3.66-3.39 (m, 1H), 1.45-1.41 (m, 5H).

I-A41c: (R)-2-ethoxypropanoic acid

To a solution of methyl (2R)-2-ethoxypropanoate (70.0 g, 529.7 mmol), in THF/MeOH/H₂O (700 mL), was added LiOH·H₂O (105.9 g, 2648.3 mmol). After stirring at 20° C. for 4 hours, HCl (2 M) (800 mL) was added, and the aqueous phase was extracted with DCM (2×400 mL). The combined organic phase was concentrated to give (R)-2-ethoxypropanoic acid (28.0 g, 234.7 mmol, 44.3% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=4.01-3.94 (m, 1H), 3.75 (s, 3H), 3.52-3.35 (m, 1H), 1.43-1.39 (m, 4H), 1.25-1.18 (m, 3H).

I-A41d: (R)-2-ethoxypropanoyl chloride

To a solution of (R)-2-ethoxypropanoic acid (4.0 g, 33.9 mmol) in THE (150 mL) was added oxalyl chloride (5.16 g, 40.6 mmol) and DMF (1.0 mL, 33.9 mmol). The mixture was stirred at 25° C. for 1 hour. The solution was used for the next step directly without further purification.

I-A36: (R)—N′-(5-chloropyrazin-2-yl)-2-ethoxypropanehydrazide

To a solution of (2R)-2-ethoxypropanoyl chloride (4.82 g, 35.3 mmol) in THE (80 mL) was added (5-chloropyrazin-2-yl)hydrazine (3.0 g, 20.8 mmol) at 0° C. After stirring at 25° C. for 1 hour, water (100 mL) was added to the mixture, and the aqueous phase was extracted with DCM (100 mL×2). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give crude product as a solid. The crude product was triturated from (PE: EtOAc=6:1, 60 ml) at 25° C. to give the product (3.3 g, 13.5 mmol, 65% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.50 (s, 1H), 8.25-8.06 (m, 1H), 7.90 (s, 1H), 4.15-3.99 (m, 1H), 3.80-3.66 (m, 1H), 3.65-3.46 (m, 1H), 1.53-1.41 (m, 3H), 1.36-1.22 (m, 3H).

I-A29: (R)-6-chloro-3-(1-ethoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine

To a mixture of (R)—N′-(5-chloropyrazin-2-yl)-2-ethoxypropanehydrazide (3.3 g, 13.5 mmol) in DCM (30 mL) was added 2-methoxypyridine (5.89 g, 54.0 mmol) and Tf₂O (7.61 g, 27.0 mmol). After stirring at 20° C. for 2 hours, water (60 mL) was added to the mixture, and the aqueous phase was extracted with DCM (30 mL×2). The combined organic phase was washed with saturated NaHCO₃ aqueous solution (60 mL), brine (60 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography (0 to 40% of EtOAc in PE) to give (R)-6-chloro-3-(1-ethoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (1.2 g, 5.02 mmol, 37% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.27-9.06 (m, 1H), 8.63-8.30 (m, 1H), 5.39-5.14 (m, 1H), 4.25-4.02 (m, 1H), 3.71-3.49 (m, 1H), 3.45-3.22 (m, 1H), 2.04 (s, 1H), 1.72 (br d, 3H), 1.29-1.18 (m, 4H).

Compound1I-19: (R)-3-(1-ethoxyethyl)-6-(6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

To a mixture of (R)-6-chloro-3-(1-ethoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (200 mg, 0.88 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (321.4 mg, 0.97 mmol) and Cs₂CO₃ (575.0 mg, 1.76 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was added Pd(dppf)Cl₂ (64.6 mg, 0.09 mmol) under N₂. After stirring at 90° C. for 2 hours, the mixture was filtered and poured into water (20 mL). The aqueous layer was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography (0 to 70% of EtOAc in PE) to give 260 mg of impure product as a solid, which was further purified by prep-HPLC (Phenomenex Gemini-NX (80×30 mm, 3 μm); A: water 10 mM NH₄HCO₃ B: CH₃CN; Gradient: from 48% to 78% of B and hole 78% for 9 min then hold 100% of B for 1.5 min; 30 mL/min; 5 injections) to give the product (128.2 mg, 0.32 mmol, 49% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.41 (d, 1H), 8.68 (d, 1H), 8.61 (d, 1H), 8.18-8.10 (m, 1H), 6.91 (d, 1H), 5.34-5.25 (m, 1H), 3.69-3.52 (m, 1H), 3.48-3.31 (m, 1H), 1.86 (s, 6H), 1.76 (d, 3H), 1.24 (t, 3H). LCMS Rt=1.024 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₈H₂₁F₃N₅O₂[M+H]+ 396.5, found 396.5.

Example I-13. Synthesis of Compound I-20: (R)-3-(1-ethoxyethyl)-6-(6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

Compound I-20: (R)-3-(1-ethoxyethyl)-6-(6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

To a mixture of (R)-6-chloro-3-(1-ethoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (200 mg, 0.88 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl) cyclobutoxy]pyridine (393.6 mg, 1.15 mmol) and Cs₂CO₃ (575.0 mg, 1.76 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added Pd(dppf)Cl₂ (64.6 mg, 0.09 mmol) under N₂. The mixture was stirred at 90° C. for 2 hours. The mixture was filtered and the filtrate was concentrated to remove dioxane. The aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude of was purified by SFC (DAICEL CHIRALCEL OD (250 mm×30 mm, 10 μm); A: CO₂ and B=EtOH 0.1% NH₃H₂O; 20% B); to give the product (190.5 mg, 0.46 mmol, 62% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.49-9.33 (m, 1H), 8.74-8.57 (m, 2H), 8.27-8.15 (m, 1H), 6.99-6.87 (m, 1H), 5.37-5.24 (m, 1H), 3.59 (s, 1H), 3.47-3.33 (m, 1H), 3.01-2.84 (m, 2H), 2.78-2.63 (m, 2H), 2.10-1.87 (m, 2H), 1.76 (d, 3H), 1.24 (t, 3H) LCMS Rt=1.449 min in 4.0 min chromatography, 50-100AB_4 min, MS ESI calcd. for C₁₉H₂₁F₃N₅O₂[M+H]⁺408.2, found 408.2.

Example I-14. Syntheses of Compounds I-21, 1-22, 1-23, 1-24: 6-(6-((S)-1-cyclopropyl-2,2,2-trifluoroethoxy)pyridin-3-yl)-3-((S)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine & 6-(6-((S)-1-cyclopropyl-2,2,2-trifluoroethoxy)pyridin-3-yl)-3-((R)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine & 6-(6-((R)-1-cyclopropyl-2,2,2-trifluoroethoxy)pyridin-3-yl)-3-((S)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine & 6-(6-((R)-1-cyclopropyl-2,2,2-trifluoroethoxy)pyridin-3-yl)-3-((R)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine. Note that stereochemistry is randomly assigned

I-A37: 6-(6-(1-cyclopropyl-2,2,2-trifluoroethoxy)pyridin-3-yl)-3-(1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine

To a mixture of 6-chloro-3-(1-methoxyethyl)-[1,2,4]triazolo[4,3-a] (92.9 mg, 0.44 mmol) and 2-(1-cyclopropyl-2,2,2-trifluoro-ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (100 mg, 0.29 mmol) and Cs₂CO₃ (189.9 mg, 0.58 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was added Pd(dppf)Cl₂ (32.0 mg, 0.04 mmol) under N₂. The mixture was stirred at 100° C. for 3 hours. The mixture was filtered, and the filtrate was concentrated to remove dioxane. The aqueous layer was extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by prep-TLC (PE/EtOAc=1:1) to afford 6-(6-(1-cyclopropyl-2,2,2-trifluoroethoxy)pyridin-3-yl)-3-(1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (50 mg, 0.13 mmol, 43.6% yield) as a solid. LCMS Rt=0.907 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₈ H₁₉F₃N₅O₂[M+H]⁺394.0, found 394.0.

Compounds I-21, I-22, I-23 & I-24: 6-(6-((S)-1-cyclopropyl-2,2,2-trifluoroethoxy)pyridin-3-yl)-3-((S)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine and 6-(6-((S)-1-cyclopropyl-2,2,2-trifluoroethoxy)pyridin-3-yl)-3-((R)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine and 6-(6-((R)-1-cyclopropyl-2,2,2-trifluoroethoxy)pyridin-3-yl)-3-((S)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine and 6-(6-((R)-1-cyclopropyl-2,2,2-trifluoroethoxy)pyridin-3-yl)-3-((R)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine

The residue was purified by SFC (DAICEL CHIRALPAK AY-H (250 mm×30 mm, 5 μm), EtOH 0.1% NH₃·H₂O; 15% B; 60 mL/min); to afford 6-(6-(1-cyclopropyl-2,2,2-trifluoroethoxy)pyridin-3-yl)-3-(1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (Fraction 1, 30 mg, 0.08 mmol) as a solid and 6-(6-(1-cyclopropyl-2,2,2-trifluoroethoxy)pyridin-3-yl)-3-(1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (Fraction 2, 50 mg, 0.13 mmol) as a solid. LCMS Rt=0.903 min in 1.5 min chromatography, 5-95AB, MS ESI calcd for C₁₈ H₁₉F₃N₅O₂[M+H]⁺394.0, found 394.0. LCMS Rt=0.910 min in 1.5 min chromatography, 5-95AB, MS ESI calcd for C₁₈ H₁₉F₃N₅O₂[M+H]⁺394.0, found 394.0.

The material of the above Fraction 1 (30 mg, 0.08 mmol) was purified by SFC (DAICEL CHIRALPAK AS (250 mm×30 mm, 10 μm), A: CO₂ B=hexane-IPA (0.1% NH₃), 20% B; 60 min; 25 mL/min); to afford 6-(6-((S)-1-cyclopropyl-2,2,2-trifluoroethoxy)pyridine-3-yl)-3-((S)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (6.60 mg, 0.02 mmol) as a solid and 6-(6-((S)-1-cyclopropyl-2,2,2-trifluoroethoxy)pyridine-3-yl)-3-((R)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (7.41 mg, 0.02 mmol) as a solid.

The material of Fraction 2 (50 mg, 0.13 mmol) was purified by SFC (DAICEL CHIRALPAK AS (250 mm×30 mm, 10 μm); A: CO₂ B=IPA 0.1% NH₃·H₂O; 15% B; 60 mL/min); to afford 6-(6-((R)-1-cyclopropyl-2,2,2-trifluoroethoxy)pyridine-3-yl)-3-((S)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (10.4 mg, 0.03 mmol) as a solid and 6-(6-((R)-1-cyclopropyl-2,2,2-trifluoroethoxy)pyridine-3-yl)-3-((R)-1-methoxyethyl)-[1,2,4]triazolo[4,3-a]pyrazine (4.91 mg, 0.01 mmol) as a solid. All chiral centers are randomly assigned.

Compound I-21:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.42 (d, 1H), 8.66 (d, 1H), 8.54 (d, 1H), 8.25-8.15 (m, 1H), 6.98 (d, 1H), 5.49-5.36 (m, 1H), 5.21 (q, 1H), 3.36 (s, 3H), 1.78 (d, 3H), 1.29-1.28 (m, 1H), 0.79-0.71 (m, 1H), 0.67-0.57 (m, 3H). LCMS Rt=1.229 min in 2.0 min chromatography, 10-80AB, MS ESI calcd for C₁₈ H₁₉F₃N₅O₂[M+H] 394.2, found 394.2. Compound I-22:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.42 (d, 1H), 8.66 (d, 1H), 8.54 (d, 1H), 8.24-8.16 (m, 1H), 6.98 (d, 1H), 5.46-5.37 (m, 1H), 5.21 (q, 1H), 3.36 (s, 3H), 1.77 (d 3H), 1.28 (s, 1H), 0.79-0.72 (m, 1H), 0.67-0.57 (m, 3H). LCMS Rt=1.217 min in 2.0 min chromatography, 10-80AB, MS ESI calcd for C₁₈ H₂₀F₄N₅O₂[M+H]+ 394.2, found 394.2. Compound I-23:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.42 (d, 1H), 8.66 (d, 1H), 8.54 (d, 1H), 8.26-8.15 (m, 1H), 7.03-6.94 (m, 1H), 5.47-5.36 (m, 1H), 5.21 (q, 1H), 3.36 (s, 3H), 1.77 (d, 3H), 1.33-1.30 (m, 1H), 0.78-0.72 (m, 1H), 0.66-0.59 (m, 3H). LCMS Rt=1.220 min in 2.0 min chromatography, 10-80AB, MS ESI calcd for C₁₈H₂₀F₄N₅O₂[M+H]⁺394.2, found 394.2. Compound I-24:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.41 (d, 1H), 8.65 (d, 1H), 8.54 (d, 1H), 8.24-8.16 (m, 1H), 6.97 (d, 1H), 5.49-5.33 (m, 1H), 5.21 (q, 1H), 3.44-3.26 (m, 3H), 1.77 (d, 3H), 1.35-1.26 (m, 1H), 0.79-0.71 (m, 1H), 0.68-0.56 (m, 3H) LCMS Rt=1.218 min in 2.0 min chromatography, 10-80AB, MS ESI calcd for C₁₈H₂₀F₄N₅O₂[M+H]⁺394.2, found 394.2.

Example 1-15: Synthesis of Intermediate I-A13

Synthesis of I-A13a: To a solution of 1-(trifluoromethyl)cyclobutanol (5 g, 35.69 mmol) in THF (300 mL) was added NaH (1.86 g, 46.4 mmol) at 0° C. over 20 minutes, and the mixture was stirred at 0° C. for 30 mins. Then to the mixture was added 5-bromo-2-fluoro-pyridine (8.48 g, 48.18 mmol), and the mixture was stirred at 30° C. for 3 hours. The mixture was quenched with sat. NH₄Cl (50 mL), then the mixture was extracted with EtOAc (50 mL). The combined organic phase was washed with brine (50 mL×3), dried over Na₂SO₄, filtered and concentrated to give the crude product (4.8 g, 15.49 mmol, 43% yield,) as an oil. LCMS Rt=0.99 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₀H₁₀BrF₃NO [M+H]⁺295.9, found 296.0. Synthesis of I-A13: A mixture of 5-bromo-2-[1-(trifluoromethyl)cyclobutoxy]pyridine (2.5 g, 8.44 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.22 g, 12.67 mmol), KOAc (1.66 g, 16.89 mmol) and Pd(dppf)Cl₂ (432.48 mg, 0.59 mmol) in 1,4-Dioxane (50 mL) was stirred at 90° C. for 12 hours under N₂. After cooling to room temperature, the mixture was concentrated to give the residue. The residue was diluted with H₂O (40 mL), and the mixture was extracted with EtOAc (40 mL×2). The combined organic phase was washed with water (40 mL) and brine (40 mL), dried over Na₂SO₄, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 1%) to give the crude product (2.65 g, 3.92 mmol, 46% yield) as an oil. ¹H NMR (CDCl₃, 400 MHz)δ_(H)=8.54 (d, 1H), 7.95 (dd, 1H), 6.74 (d, 1H), 2.99-2.81 (m, 2H), 2.75-2.53 (m, 2H), 2.13-1.78 (m, 2H), 1.34 (s, 12H).

Example 1-16. Synthesis of Intermediate I-A42

I-A42a: 1-cyclopropyl-2,2,2-trifluoroethan-1-ol

To a stirred solution of cyclopropanecarbaldehyde (5.0 g, 71.34 mmol) in THF (50.0 mL) was added trimethyl(trifluoromethyl)silane (11.16 g, 78.47 mmol) and TBAF (1.0 M in THF, 7.14 mL, 7.1 mmol) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 4 hours. To the reaction mixture TBAF (1.0 M in THF, 142.6 mL, 142.6 mmol) was added at room temperature and stirred for 30 min. The reaction mixture was treated with water (50.0 mL) and extracted with diethyl ether (2×100 mL). The organic layer was washed with 10% NaHCO₃ solution (50.0 mL) and brine (50 mL). The organic layer was dried over anhydrous Na₂SO₄ and concentrated at 30° C. to afford 1-cyclopropyl-2,2,2-trifluoroethan-1-ol (3.2 g), which was used for the next step without further purification.

I-A42b: 5-bromo-2-(1-cyclopropyl-2,2,2-trifluoroethoxy)pyridine

To a stirred solution of 1-cyclopropyl-2,2,2-trifluoroethan-1-ol (3.0 g, 21.41 mmol) in THF (30.0 mL) at 0° C. was added NaH (60% in mineral oil, 1.28 g, 32.12 mmol) in small portions. The reaction mixture was stirred for 10 min and 5-bromo-2-fluoro-pyridine (3.77 g, 21.41 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction mixture was cooled to 10° C. and treated with ice water (100 mL). The reaction mixture was extracted with EtOAc (2×100 mL). The organic layer was washed with brine (80 mL), dried over anhydrous Na₂SO₄ and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel with PE to afford 5-bromo-2-(1-cyclopropyl-2,2,2-trifluoroethoxy)pyridine (3.1 g, 10.47 mmol, 48% yield). LCMS: 296.0 (M+H)+ and 298.0 (M+2+H)+, Rt 2.90 min; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

I-A42: 2-(1-cyclopropyl-2,2,2-trifluoroethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a stirred solution of 5-bromo-2-(1-cyclopropyl-2,2,2-trifluoroethoxy)pyridine (3.1 g, 10.47 mmol) and bis(pinacolato)diboron (3.46 g, 13.61 mmol) in 1,4-dioxane (30 mL) was added potassium acetate (1.72 g, 20.94 mmol). Pd(dppf)Cl₂.DCM (0.86 g, 1.05 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 90° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered through celite. The reaction mixture was treated with ice water (50 mL) and extracted with EtOAc (2×50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel with 4% EtOAc/PE to afford 2-(1-cyclopropyl-2,2,2-trifluoroethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.2 g, 9.3 mmol, 89% yield). LCMS: 344.1 (M+H)+, Rt 3.18 min; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

Example II-1. Synthesis of Compound II-1: 6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-3-(1-methoxycyclopropyl)-[1,2,4]triazolo[4,3-a]pyrazine

II-A2: Methyl 1-methoxycyclopropane-1-carboxylate

To a stirred solution of methyl 1-hydroxycyclopropane-1-carboxylate (3.0 g, 25.84 mmol) in THE (10.0 mL) was added NaH (60% in mineral oil, 1.13 g, 28.42 mmol) at 0° C. and stirred for 30 mins. To the reaction mixture iodomethane (3.67 g, 25.84 mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled to 10° C. and treated with ice cold water (50 mL). The reaction mixture was extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (40 mL), dried over anhydrous Na₂SO₄ and concentrated to afford methyl 1-methoxycyclopropane-1-carboxylate (2.0 g), which was used for the next step without further purification.

II-A3: 1-methoxycyclopropane-1-carboxylic acid

To a stirred solution of methyl 1-methoxycyclopropane-1-carboxylate (1.0 g, 7.68 mmol) in THF (6.0 mL) and methanol (6.0 mL) was added 2.0 M KOH (10.0 mL). The reaction mixture was stirred at room temperature for 60 hours. The reaction mixture was concentrated, treated with water (20 mL) and extracted with ethyl acetate (30 mL). The aqueous layer treated with 6.0N HCl (5.0 mL) and extracted with diethyl ether (2×50 mL). The organic layer was washed with brine (40 mL), dried over anhydrous Na₂SO₄ and concentrated to afford 1-methoxycyclopropane-1-carboxylic acid (650 mg), which was used for the next step without further purification.

II-A5: N′-(5-chloropyrazin-2-yl)-1-methoxycyclopropane-1-carbohydrazide

To a stirred solution of 1-methoxycyclopropane-1-carboxylic acid (275 mg, 2.37 mmol) in DCM (6.0 mL) was added DIPEA (1.23 mL, 7.11 mmol) followed by PyBOP (1.85 g, 3.55 mmol) and 2-chloro-5-hydrazinylpyrazine (340.0 mg, 2.37 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was treated with water (30 mL) and extracted with ethyl acetate (2×30 mL). The organic layer was washed with brine (40 mL), dried over anhydrous Na₂SO₄ and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel with 20% ethyl acetate/PE to afford N′-(5-chloropyrazin-2-yl)-1-methoxycyclopropane-1-carbohydrazide (220 mg, 0.90 mmol, 37% yield). LCMS: 243.1 (M+H), Rt 1.55 min; Column: Atlantis dC-18 (50×4.6 mm), 5 μm; Mobile Phase: A: 0.1% HCOOH in water: CH₃CN (95:5), B: CH₃CN; Flow Rate: 1.5 mL/min.

II-A7: 6-chloro-3-(1-methoxycyclopropyl)-[1,2,4]triazolo[4,3-a]pyrazine

To a stirred solution of N′-(5-chloropyrazin-2-yl)-1-methoxycyclopropane-1-carbohydrazide (520 mg, 2.1 mmol) in DCM (6.0 mL) was added 2-methoxypyridine (461 mg, 4.23 mmol) and trifluoromethanesulfonic anhydride (0.43 mL, 2.54 mmol) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was treated with 10% sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (2×25 mL). The organic layer was washed with brine (20 mL), dried over Na₂SO₄ and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel with 20% EtOAc/PE to afford 6-chloro-3-(1-methoxycyclopropyl)-[1,2,4]triazolo[4,3-a]pyrazine (80 mg, 0.35 mmol, 16% yield). LCMS: 225.1 (M+H), Rt 1.61 min; Column: Atlantis dC-18 (50×4.6 mm), 5 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

Compound II-1: 6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-3-(1-methoxycyclopropyl)-[1,2,4]triazolo[4,3-a]pyrazine

To a stirred solution of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (120 mg, 0.37 mmol) and 6-chloro-3-(1-methoxycyclopropyl)-[1,2,4]triazolo[4,3-a]pyrazine (80 mg, 0.35 mmol) in 1,4-dioxane (3.0 mL) was added water (0.5 mL) and Cs₂CO₃ (243 mg, 0.75 mmol). Pd(dppf)Cl₂.DCM (29 mg, 0.04 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC to afford the product (34 mg, 0.08 mmol, 25% yield) as a solid. Prep-HPLC method: Rt 18.1; Column: X-Bridge (150×19 mm), 5.0 μm; 0.1% TFA in water/acetonitrile; Flow Rate: 15.0 mL/min. HPLC: Rt 4.45 min; Column: X-Bridge C₈ (50×4.6) mm, 3.5 μm; Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 384.2 (M+H), Rt 2.13 min; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min. ¹H NMR (400 MHz, DMSO-d₆):δ_(H)=9.57 (d, 1H), 9.00 (d, 1H), 8.78 (d, 1H), 8.57 (dd, 1H), 5.18 (q, 2H), 3.19 (s, 3H), 1.44-1.40 (m, 2H), 1.31-1.27 (m, 2H).

Example II-2. Synthesis of Compound 11-2: (R)-6-(5-fluoro-6-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)-3-(1-methoxycyclopropyl)-[1,2,4]triazolo[4,3-a]pyrazine

II-A10: (R)-5-bromo-3-fluoro-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine

To a solution of (R)-1,1,1-trifluoropropan-2-ol (9.64 mmol) in THE was added NaH (578 mg, 14.46 mmol) portion wise at 0° C. and stirred for 30 min. 5-bromo-2,3-difluoro-pyridine (1.36 g, 7.0 mmol) was added to the reaction mixture slowly at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was cooled to 10° C., treated with ice water (10 mL) and extracted with ethyl acetate (2×30 mL). The organic layer was washed with brine (30 mL), dried over Na₂SO₄ and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel with 20% EtOAc/PE to afford (R)-5-bromo-3-fluoro-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine (1.6 g) as a liquid. It was used for the next step without further purification.

II-A11: (R)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine

To a stirred solution of (R)-5-bromo-3-fluoro-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine (1.6 g, 5.55 mmol) and bis(pinacolato)diboron (1.83 g, 7.22 mmol) in 1,4-dioxane (20.0 mL) was added potassium acetate (1.09 g, 11.11 mmol). Pd(dppf)Cl₂.DCM (0.68 g, 0.83 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 85° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel with 6% ethyl acetate/PE to afford the product (300 mg, 0.89 mmol, 16% yield) as a solid. LCMS: 336.1 (M+H), Rt 2.93 min; Column: Atlantis dC18 (50×4.6 mm), 5.0 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

Compound II-2: (R)-6-(5-fluoro-6-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)-3-(1-methoxycyclopropyl)-[1,2,4]triazolo[4,3-a]pyrazine

To a stirred solution of (R)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine (123 mg, 0.37 mmol) and 6-chloro-3-(1-methoxycyclopropyl)-[1,2,4]triazolo[4,3-a]pyrazine (75.0 mg, 0.33 mmol) in 1,4-dioxane (10.0 mL) was added water (1.0 mL) and cesium carbonate (217 mg, 0.67 mmol). Pd(dppf)Cl₂.DCM (27 mg, 0.03 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC to afford the product (30 mg, 0.075 mmol, 22% yield). Prep-HPLC method: Rt 8.37; Column: X-Bridge C-18 (150×19 mm), 5.0 μm; 0.1% TFA in water/acetonitrile; Flow Rate: 15.0 mL/min. HPLC: Rt 4.76 min; Column: X-Bridge C₈ (50×4.6) mm, 3.5 μm; Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 398.1 (M+H), Rt 2.33 min; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min. ¹H NMR (400 MHz, DMSO-d₆):δ_(H)=9.57 (d, 1H), 9.00 (d, 1H), 8.77 (d, 1H), 8.56 (dd, 1H), 6.05-6.01 (m, 1H), 3.20 (s, 3H), 1.55 (d, 3H), 1.43-1.41 (m, 2H), 1.31-1.29 (m, 2H).

Example II-3. Synthesis of Compound 11-3: (S)-6-(5-fluoro-6-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)-3-(1-methoxycyclopropyl)-[1,2,4]triazolo[4,3-a]pyrazine

II-A21: (S)-5-bromo-3-fluoro-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine

To a solution of 2(S)-1,1,1-trifluoropropan-2-ol (35.07 mmol) in THE (30.0 mL) was added NaH (1.54 g, 38.57 mmol) portion wise at 0° C. and stirred for 30 min. 5-bromo-2,3-difluoro-pyridine (6.8 g, 35.07 mmol) was added to the reaction mixture slowly at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was cooled to 10° C., treated with ice water (30 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (40 mL), dried over Na₂SO₄ and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel with 20% EtOAc/PE to afford the product (4 g, 13.9 mmol, 39% yield). LCMS: 288.0 (M+H) and 290.0 (M+2+H), Rt 2.77 min; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

II-A12: (S)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine

To a stirred solution of (S)-5-bromo-3-fluoro-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine (2.0 g, 6.94 mmol) and bis(pinacolato)diboron (1.94 g, 7.64 mmol) in 1,4-dioxane (25.0 mL) was added potassium acetate (1.36 g, 13.89 mmol). Pd(dppf)Cl₂.DCM (0.57 g, 0.69 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 80° C. for 12 hours. The reaction mixture was cooled to room temperature, filtered through Celite and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel with 10% ethyl acetate/PE to afford the product (1.06 g, 3.17 mmol, 45% yield). LCMS: 336.2 (M+H), Rt 3.09 min; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

Compound I-3: (S)-6-(5-fluoro-6-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)-3-(1-methoxycyclopropyl)-[1,2,4]triazolo[4,3-a]pyrazine

To a stirred solution of (S)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine (98 mg, 0.29 mmol) and 6-chloro-3-(1-methoxycyclopropyl)-[1,2,4]triazolo[4,3-a]pyrazine (60 mg, 0.27 mmol) in 1,4-dioxane (2.7 mL) was added water (0.30 mL) and Cs₂CO₃ (174 mg, 0.53 mmol). Pd(dppf)Cl₂.DCM (22 mg, 0.03 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 90° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered through Celite. The reaction mixture was treated with water (30 mL) and extracted with ethyl acetate (2×30 mL).

The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated to give a crude product. The crude product was purified by preparative HPLC to afford the product (10 mg, 0.025 mmol, 9% yield) as a solid. Prep. HPLC method: Rt 13.06; Column: Sunfire C₁₈ (150×19 mm), 5.0 μm; Mobile phase: 0.1% TFA in water/acetonitrile; Flow Rate: 15.0 mL/min. HPLC: Rt 4.77 min; Column: X-Bridge C₈ (50×4.6) mm, 3.5 μm; Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 398.1 (M+H), Rt 2.34 min; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min. ¹H NMR (400 MHz, DMSO-d₆):δ_(H)=9.57 (d, 1H), 8.99 (d, 1H), 8.77 (d, 1H), 8.56 (dd, 1H), 6.06-5.99 (m, 1H), 3.20 (s, 3H), 1.55 (d, 3H), 1.44-1.41 (m, 2H), 1.31-1.28 (m, 2H).

Example II-4. Synthesis of Compound 11-4: 6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-3-(2-methoxypropan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazine

II-A14: N′-(5-chloropyrazin-2-yl)-2-methoxy-2-methylpropanehydrazide

To a stirred solution of 2-chloro-5-hydrazinylpyrazine (5.0 g, 34.59 mmol) in DCM (100 mL) was added 2-methoxy-2-methylpropanoic acid (4.49 g, 38.05 mmol) followed by PyBOP (27.0 g, 51.88 mmol) and DIPEA (12.05 mL, 69.18 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was treated with water (60 mL) and extracted with DCM (2×100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel with 18% EtOAc/PE to afford the product (4.77 g, 19.56 mmol, 56% yield). LCMS: 245.1 (M+H), Rt 1.24 min; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

II-A16: 6-chloro-3-(2-methoxypropan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazine

To a stirred solution of N′-(5-chloropyrazin-2-yl)-2-methoxy-2-methylpropanehydrazide (2.29 g, 9.39 mmol) in DCM (24.0 mL) was added 2-methoxypyridine (1.97 mL, 18.78 mmol) and trifluoromethanesulfonic anhydride (1.9 mL, 11.27 mmol) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. To the reaction mixture 2-methoxypyridine (1.97 mL, 18.78 mmol) and trifluoromethanesulfonic anhydride (1.9 mL, 11.27 mmol) were added and stirred for 16 h at room temperature. The reaction mixture was treated with water (50 mL) and extracted with DCM (2×60 mL). The organic layer was washed with brine (30 mL), dried over Na₂SO₄ and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel with 55% EtOAc/PE to afford the product (180 mg, 0.80 mmol, 8% yield). LCMS: 227.1 (M+H), Rt 1.36 min; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

Compound 11-4: 6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-3-(2-methoxypropan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazine

To a stirred solution of 6-chloro-3-(2-methoxypropan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazine (60 mg, 0.27 mmol) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (171 mg, 0.54 mmol) in 1,4-dioxane (1.8 mL) was added water (0.2 mL) and Cs₂CO₃ (174 mg, 0.54 mmol). Pd(dppf)Cl₂.DCM (22 mg, 0.03 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, filtered through Celite and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC to afford the product (57 mg, 0.14 mmol, 54% yield) as a solid. Prep-HPLC method: Rt 13.7; Column: X-Bridge C-18 (150×19 mm), 5.0 μm; 0.1% TFA in water/acetonitrile; Flow Rate: 15.0 mL/min. LCMS: 386.1 (M+H), Rt 2.24 min, 97.6%; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min. ¹H NMR (400 MHz, CD₃0D):δ_(H)=9.44 (d, 1H), 8.93 (d, 1H), 8.68 (d, 1H), 8.30 (dd, 1H), 5.06 (q, 2H), 3.18 (s, 3H), 1.85 (s, 6H).

Example II-5. Synthesis of Compound 11-5: 3-(2-methoxypropan-2-yl)-6-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

To a stirred solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (110 mg, 0.36 mmol) and 6-chloro-3-(2-methoxypropan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazine (82 mg, 0.36 mmol) in 1,4-dioxane (2.7 mL) was added water (0.3 mL) and Cs₂CO₃ (214 mg, 0.66 mmol). Pd(PPh₃)2Cl₂.DCM (0.27 mg, 0.033 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 90° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered through Celite. The reaction mixture was treated with water (30 mL) and extracted with ethyl acetate (2×30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel with 18% ethyl acetate/PE to afford the product (45 mg, 0.12 mmol, 33% yield) as a solid. LCMS: 368.1 (M+H), Rt 2.11 min, 97.5%; Column: ZORBAX XDB C-18 (50×4.6 mm), 5.0 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min. ¹H NMR (400 MHz, DMSO-d₆):δ_(H)=9.57 (d, 1H), 8.87 (d, 1H), 8.81 (d, 1H), 8.45 (dd, 1H), 7.17 (d, 1H), 5.09 (q, 2H), 3.06 (s, 3H), 1.77 (s, 6H).

Example II-6. Synthesis of Compound 11-6: 3-(1-methoxy-1-methyl-ethyl)-6-[6-[rac-(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

To a stirred solution of 6-chloro-3-(2-methoxypropan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.44 mmol) and (R)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine (154 mg, 0.49 mmol) in 1,4-dioxane (10 mL) was added water (1.0 mL) and K₂CO₃ (744 mg, 2.29 mmol). Pd(PPh₃)Cl₂ (0.3 g, 0.044 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC to afford the product (45 mg, 0.11 mmol, 26% yield) as a solid. Prep-HPLC method: Rt 12.1; Column: X-Bridge C-18 (150×19 mm), 5.0 μm; 0.1% TFA in water/acetonitrile; Flow Rate: 15.0 mL/min. LCMS: 381.9 (M+H), Rt 2.32 min, 99.8%; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min. ¹H NMR (400 MHz, CDCl₃): δ_(H) =9.45 (d, 1H), 8.73-8.70 (m, 2H), 8.23 (dd, 1H), 6.99 (dd, 1H), 5.91-5.87 (m, 1H), 3.16 (s, 3H), 1.87 (s, 6H), 1.56 (d, 3H).

Example II-7. Synthesis of Compound 11-7: (S)-3-(chlorodifluoromethyl)-6-(6-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

To a stirred solution of (S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((1,1,1-trifluoropropan-2-yl)

oxy)pyridine (154 mg, 0.48 mmol) and 6-chloro-3-(2-methoxypropan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.44 mmol) in 1,4-dioxane (2.7 mL) was added water (0.30 mL) and Cs₂CO₃ (288 mg, 0.88 mmol). Pd(dppf)Cl₂.DCM (36 mg, 0.04 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, filtered through Celite and concentrated under reduced pressure to give a crude product. The reaction mixture was treated with water (20 mL) and extracted with EtOAc (2×30 mL). The organic layer was washed with brine (20 mL), dried over Na₂SO₄ and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel with 40% EtOAc/PE to afford the product (18 mg, 0.046 mmol, 10% yield) as a solid. LCMS: 382.1 (M+H), Rt 2.34 min, 98.0%; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min. ¹H NMR (400 MHz, DMSO-d6):δ_(H)=9.57 (d, 1H), 8.86 (d, 1H), 8.80 (d, 1H), 8.43 (dd, 1H), 7.12 (d, 1H), 6.00-5.96 (m, 1H), 3.06 (s, 3H), 1.77 (s, 6H), 1.51 (d, 3H).

Example II-8. Synthesis of Compound 11-8: (R)-6-(5-fluoro-6-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)-3-(2-methoxypropan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazine

To a stirred solution of (R)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine (100 mg, 0.29 mmol) and 6-chloro-3-(2-methoxypropan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazine (128 mg, 0.57 mmol) in 1,4-dioxane (1.8 mL) was added water (0.2 mL) and Cs₂CO₃ (186 mg, 0.57 mmol). Pd(dppf)Cl₂.DCM (24 mg, 0.03 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, filtered through Celite and concentrated under reduced pressure. The reaction mixture was treated with water (20 mL) and extracted with ethyl acetate (2×25 mL). The organic layer was washed with brine (20 mL), dried over Na₂SO₄ and concentrated to give a crude product. The crude product was purified by preparative HPLC to afford the product (57 mg, 0.14 mmol, 48% yield) as a solid. Prep-HPLC method: Rt 10.15; Column: YMC C-18 (150×19 mm), 5.0 μm; 0.1% TFA in water/acetonitrile; Flow Rate: 15.0 mL/min. LCMS: 400.0 (M+H), Rt 2.39 min, 98.0%; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min. ¹H NMR (400 MHz, CD₃0D):δ_(H)=9.44 (d, 1H), 8.93 (d, 1H), 8.67 (d, 1H), 8.28 (dd, 1H), 6.05-5.98 (m, 1H), 3.18 (s, 3H), 1.85 (s, 6H), 1.59 (d, 3H).

Example II-9. Synthesis of Compound 11-9: (S)-6-(5-fluoro-6-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)-3-(2-methoxypropan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazine

To a stirred solution of (S)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine (163 mg, 0.49 mmol) and 6-chloro-3-(2-methoxypropan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.44 mmol) in 1,4-dioxane (2.7 mL) was added water (0.30 mL) and Cs₂CO₃ (287 mg, 0.88 mmol). Pd(dppf)Cl₂.DCM (36 mg, 0.044 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 90° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered through Celite. The reaction mixture was treated with water (30 mL) and extracted with ethyl acetate (2×30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated to give a crude product. The crude product was purified by preparative HPLC to afford the product (82 mg, 0.20 mmol, 45% yield) as a solid. Prep. HPLC method: Rt 10.35; Column: X-Bridge C₁₈ (150×19 mm), 5.0 μm; Mobile phase: 0.1% TFA in water/acetonitrile; Flow Rate: 15.0 mL/min. LCMS: 400.1 (M+H), Rt 2.37 min, 98.0%; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min. ¹H NMR (400 MHz, DMSO-d₆): δ_(H) =9.57 (d, 1H), 8.87 (d, 1H), 8.72 (d, 1H), 8.50 (dd, 1H), 6.06-5.99 (m, 1H), 3.05 (s, 3H), 1.78 (s, 6H), 1.55 (d, 3H).

Example II-10. Synthesis of Compound 11-10: 6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-3-(1-methoxy-1-methyl-ethyl)-[1,2,4]triazolo[4,3-a]pyrazine

To a mixture of 6-chloro-3-(1-methoxy-1-methyl-ethyl)-[1,2,4]triazolo[4,3-a]pyrazine (220 mg, 0.97 mmol) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (339 mg, 0.97 mmol) and Cs₂CO₃ (632 mg, 1.94 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added Pd(dppf)Cl₂ (71 mg, 0.10 mmol) under N₂. The mixture was stirred at 90° C. for 2 hours. The mixture was filtered and the filtrated was concentrated to remove dioxane. The aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give a crude product. The crude product was purified by prep-HPLC (Phenomenex Gemini-NX 80×30 mm, 3 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 42-72% B over 9.5 minutes) to afford the product (158.4 mg, 0.38 mmol, 39% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.43 (s, 1H), 8.71 (s, 1H), 8.49 (s, 1H), 8.01 (d, 1H), 3.16 (s, 3H), 1.88 (s, 6H), 1.85 (s, 6H). LCMS Rt=1.21 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₈ H₂₀F₄N₅O₂[M+H]⁺414.2, found 414.1.

Example II-11: Synthesis of Intermediates Synthesis of II-A6: 3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

B: To a suspension of NaH (2.94 g, 73.56 mmol) in THE (50 mL) was added 2,2,2-trifluoroethanol (7.36 g, 73.56 mmol) slowly at 20° C., and the mixture was stirred for 1 hour. 5-chloro-2,3-difluoro-pyridine (10 g, 66.88 mmol) was then added, and the mixture was stirred at 20° C. for another 4 hours. The mixture was quenched with saturated aqueous NH₄Cl (50 mL) and extracted with EtOAc (100 mL×2). The combined organic phase was washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated to afford B (15000 mg, 65.34 mmol) as an oil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=7.83 (d, 1H), 7.38 (dd, 1H), 4.73 (q, 2H). II-A6: A mixture of B (8 g, 34.85 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (26.55 g, 104.55 mmol), K₃PO₄ (14.79 g, 69.7 mmol), SPhos (4.29 g, 10.45 mmol) and Pd(OAc)₂ (782.4 mg, 3.48 mmol) in 1,4-dioxane (250 mL) was stirred at 85° C. for 16 hours. After cooling to room temperature, the mixture was filtered through Celite and eluted with EtOAc (50 mL×2). The filtrate was concentrated and diluted with EtOAc (200 mL), washed with water (100 mL×2) and brine (100 mL), dried over Na₂SO₄, filtered, and concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0 to 10% to 40%) to afford the product (3 g, 4.6021 mmol) as an oil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.26 (d, 1H), 7.72 (dd, 1H), 4.87 (q, 2H), 1.35 (s, 12H). LCMS Rt=0.94 min using Method B, MS ESI calcd. for C₁₃H₁₇BF₄NO₃ [M+H]⁺322.1, found 322.3. Synthesis of II-A17: (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine)

A mixture of 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine (7 g, 27.34 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (7.64 g, 30.08 mmol), KOAc (5.37 g, 54.68 mmol) and Pd(dppf)Cl₂ (1 g, 1.37 mmol) in 1,4-dioxane (80 mL) was stirred at 85° C. for 12 hours under N₂. After cooling to room temperature, the mixture was filtered through Celite and then the filtrate was concentrated to give a crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 5%) to give the product (8 g, 26.4 mmol, 96% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.53 (s, 1H), 8.00 (dd, 1H), 6.84 (d, 1H), 4.80 (q, 2H), 1.35 (s, 12H).

Synthesis of II-A18: ((R)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine)

To a stirred solution of (R)-5-bromo-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine (3.1 g, 11.5 mmol) and bis(pinacolato)diboron (3.79 g, 14.92 mmol) in 1,4-dioxane (35.0 mL) was added potassium acetate (2.25 g, 22.96 mmol). Pd(dppf)Cl₂.DCM (1.41 g, 1.72 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 90° C. for 12 hours. The reaction mixture was cooled to room temperature, filtered through Celite and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel with 6% ethyl acetate/PE to afford (R)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine (2.8 g, 8.83 mmol, 76% yield) as a solid. LCMS: 318.0 (M+H), Rt 4.04 min; Column: ZORBAX Extend (50×4.6 mm), 5 μm; Mobile Phase: A: 10 mM Ammonium acetate in water, B: ACN; Flow Rate: 1.2 mL/min.

Synthesis of II-A19: ((S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine)

To a stirred solution of (S)-5-bromo-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine (0.5 g, 1.85 mmol) and bis(pinacolato)diboron (0.52 g, 2.04 mmol) in 1,4-dioxane (5.0 mL) was added potassium acetate (0.36 g, 3.7 mmol). Pd(dppf)Cl₂.DCM (0.15 g, 0.19 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 80° C. for 12 hours. The reaction mixture was cooled to room temperature, filtered through Celite and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel with 10% ethyl acetate/PE to afford (S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine (302 mg, 0.95 mmol, 51% yield). LCMS: 318.1 (M+H), Rt 3.04 min; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

Synthesis of II-A24: (3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine)

A mixture of 5-bromo-3-fluoro-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (6.3 g, 20.86 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.83 g, 22.94 mmol), Pd(dppf)Cl₂ (1.53 g, 2.09 mmol) and KOAc (4.09 g, 41.71 mmol) in 1,4-dioxane (100 mL) was stirred at 90° C. for 2.5 hours. After cooling to 25° C., the suspension was diluted with EtOAc (50 mL), filtered through silica gel and eluted with EtOAc (50 mL). The combined filtrates were concentrated to give a crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10%) to give the product (5.7 g, 16.33 mmol, 78% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.26 (s, 1H), 7.67 (d, 1H), 1.83 (s, 6H), 1.34 (s, 12H). LCMS Rt=1.06 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₅H₂₁BF₄NO₃ [M+H]⁺350.1, found 350.0.

Example II-12. Synthesis of Compound TI-11: 3-(2-ethoxypropan-2-yl)-6-(5-fluoro-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

II-A26: 2-ethoxy-2-methylpropanoyl chloride

To a solution of 2-ethoxy-2-methyl-propanoic acid (2 g, 15.13 mmol) in THE (20 mL) was added (COCI)₂ (1.56 mL, 18.2 mmol) and DMF (0.20 mL) at 0° C. under N₂. The mixture was stirred at 25° C. under N₂ for 1 hour. The solution was used in the next step directly.

II-A27: N′-(5-chloropyrazin-2-yl)-2-ethoxy-2-methylpropanehydrazide

To the above solution was added 2-ethoxy-2-methyl-propanoyl chloride (2.28 g, 15.1 mmol) in THE (20 mL) at 0° C. under N₂. After stirring at 25° C. under N₂ for 2 hours, the mixture was poured into H₂O (50 mL) and extracted with EtOAc (30×2 mL). The combined organic phases were washed with NaHCO₃ (50 mL), brine (50 mL), dried over Na₂SO₄, filtered, and concentrated to give N′-(5-chloropyrazin-2-yl)-2-ethoxy-2-methyl-propanehydrazide (3 g, 9.28 mmol, 61.3% yield) as a solid. LCMS Rt=0.816 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₀H₁₆C₁N₄O₂[M+H]⁺258.9, found 258.9.

II-A28: 6-chloro-3-(2-ethoxypropan-2-yl)-[1,2, 4]triazolo[4, 3-a] pyrazine

To a solution of N′-(5-chloropyrazin-2-yl)-2-ethoxy-2-methyl-propanehydrazide (3 g, 11.6 mmol) in DCM (10 mL) was added 2-methoxypyridine (5.06 g, 46.4 mmol) and Tf₂O (3.92 mL, 23.2 mmol) under N₂. After stirring at 20° C. for 2 hours. The reaction was poured into water (50 mL) and extracted with DCM (30 mL×2). The combined organic layer was washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography (15 to 25% of EtOAc in PE) to give 6-chloro-3-(1-ethoxy-1-methyl-ethyl)-[1,2,4]triazolo[4,3-a]pyrazine (600 mg, 1.50 mmol, 13% yield) as an oil. LCMS Rt=0.818 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₀H₁₄C₁N₄O₁[M+H]⁺240.9, found 240.9.

Compound II-All: 3-(2-ethoxypropan-2-yl)-6-(5-fluoro-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

To a solution of 6-chloro-3-(1-ethoxy-1-methyl-ethyl)-[1,2,4]triazolo[4,3-a]pyrazine (600 mg, 2.49 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was added 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (957.4 mg, 2.74 mmol), Cs₂CO₃ (1.62 g, 4.99 mmol) and Pd(dppf)Cl₂ (182.4 mg, 0.25 mmol) under N₂. After stirring at 90° C. for 16 hours, the mixture was filtered, and the filtrate was concentrated to remove dioxane. The aqueous layer was extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography (20% to 30% of EtOAc in PE) to give the product (300 mg,0.63 mmol, 25% yield) as an oil, which was purified by prep-HPLC (Phenommenex Genmini-NX 80 mm×30 mm, 3 μm; Condition: A=water (10 mM NH₄HCO₃) B=ACN; 51-81% B) to give 3-(1-ethoxy-1-methyl-ethyl)-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (173.54 mg, 0.41 mmol, 58% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.41 (d, 1H), 8.79 (d, 1H), 8.45 (d, 1H), 8.01-7.96 (m, 1H), 3.32-3.23 (m, 2H), 1.86 (s, 6H), 1.84 (s, 6H), 1.23-1.17 (m, 3H). ¹⁹F NMR (376.5 MHz, CDCl₃)δ_(F)=−83.963,-135.024. LCMS Rt=1.091 min in 2.0 min chromatography, 30-90AB, MS ESI calcd. for C₁₉H₂₂ F₄N₅O₂[M+H]⁺428.1, found 428.1.

Example II-13. Synthesis of Compound II-12: 6-(5-fluoro-6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-3-(2-methoxypropan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazine

Compound II-12: 6-(5-fluoro-6-(1-(trifluoromethyl)cyclobutoxy)pyridin-3-yl)-3-(2-methoxypropan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazine

To a mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl)cyclobutoxy]pyridine (262.9 mg, 0.73 mmol) and 6-chloro-3-(1-methoxy-1-methyl-ethyl)-[1,2,4]triazolo[4,3-a]pyrazine (150 mg, 0.66 mmol) and Cs₂CO₃ (431.2 mg, 1.32 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added Pd(dppf)Cl₂ (48.4 mg, 0.07 mmol) under N₂. After stirring at 90° C. for 16 hours, the mixture was filtered, and the filtrate was concentrated to remove dioxane. The aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude mixture was purified by prep-HPLC (Phenomenex Gemini-NX 80×30 mm, 3 μm, A=water (10 mM NH₄HCO₃) B=ACN), 47-77% B over 9 min., 100% for 2.5 min.) to give 6 the product (13.59 mg, 0.03 mmol, 5% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.41 (d, 1H), 8.71 (d, 1H), 8.46 (d, 1H), 8.03 (dd, 1H), 3.14 (s, 3H), 2.99-2.85 (m, 2H), 2.81-2.66 (m, 2H), 2.09-1.91 (m, 2H), 1.84 (s, 6H). LCMS Rt=1.28 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₉H₂₀F₄N₅O₂[M+H]+ 426.1, found 426.2

Example II-14. Synthesis of Compound 11-13: 3-(1-methoxy-1-methyl-ethyl)-6-[6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

Compound II-13: 3-(1-methoxy-1-methyl-ethyl)-6-[6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

To a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl)cyclobutoxy]pyridine (348.2 mg, 1.01 mmol) and 6-chloro-3-(1-methoxy-1-methyl-ethyl)-[1,2,4]triazolo[4,3-a]pyrazine (200 mg, 0.88 mmol) and Cs₂CO₃ (574.9 mg, 1.76 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added Pd(dppf)Cl₂ (64.6 mg, 0.09 mmol) under N₂. After stirring at 90° C. for 3 hours, the mixture was filtered, poured into water (30 ml), and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude mixture was purified by flash column chromatography (0 to 50% of EtOAc in PE) to give the product (230 mg, 0.56 mmol, 64% yield) as an oil. The 3-(1-methoxy-1-methyl-ethyl)-6-[6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (230 mg, 0.56 mmol) was purified by HPLC (Phenomenex Gemini-NX 80×30 mm, 3 μm A=water (10 mM NH₄HCO₃) B=ACN, 47-77% B over 9 min., 100% B for 1.5 min., 30 mL/min, 5 injections) to give 3-(1-methoxy-1-methyl-ethyl)-6-[6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (10.6 mg, 0.03 mmol) as a solid. ¹H NMR (400 MHz, CDCl₃)^(6H)=9.43 (d, 1H), 8.69 (d, 2H), 8.26-8.16 (m, 1H), 6.96-6.87 (m, 1H), 3.14 (s, 3H), 2.99-2.85 (m, 2H), 2.77-2.64 (m, 2H), 2.09-1.90 (m, 2H), 1.84 (s, 6H). ¹⁹F NMR (400 MHz, CDCl₃)δ_(F) =−81.188. LCMS Rt=1.039 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₉H₂₁F₃N₅O₂[M+H]+ 408.1, found 408.1.

Example II-15. Synthesis of Compound 11-14: 3-(1-methoxy-1-methyl-ethyl)-6-[6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

II-A31: 2-methoxy-2-methyl-propanoyl chloride

To a solution of 2-methoxy-2-methyl-propanoic acid (3.00 g, 25.0 mmol) in THF (30 mL) was added DMF (0.1 mL, 25 mmol) and (COCI)₂ (2.4 mL, 28 mmol) at 0° C. under N₂. The mixture was stirred at 25° C. under N₂ for 1 hour. The solution was used directly for the next step without characterization.

II-A14: N′-(5-chloropyrazin-2-yl)-2-methoxy-2-methyl-propanehydrazide

To a solution of (5-chloropyrazin-2-yl)hydrazine (3.00 g, 21.0 mmol) in THF (30 mL) was added 2-methoxy-2-methyl-propanoyl chloride (3.40 g, 25.0 mmol) at 25° C. The reaction was stirred at 25° C. for 2 hours. The reaction was quenched with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layer was washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated in vacuum to give N′-(5-chloropyrazin-2-yl)-2-methoxy-2-methyl-propanehydrazide (4.00 g, 79.0% yield), which was used directly in the next step. LCMS R_(t)=0.778 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₉H₁₄C₁N₄02 [M+H]⁺244.9, found 244.9.

II-A16: 6-chloro-3-(1-methoxy-1-methyl-ethyl)-[1,2,4]triazolo[4,3-a]pyrazine

To a solution of N′-(5-chloropyrazin-2-yl)-2-methoxy-2-methyl-propanehydrazide (4.00 g, 16.0 mmol) in DCM (40 mL) was added 2-methoxypyridine (11.2 g, 103.0 mmol) and Tf₂O (8.30 mL, 49.0 mmol) at 0° C. After stirring at 25° C. for 4 hours, the reaction was quenched with water (50 mL) and extracted with DCM (2×50 mL). The combined organic layer was washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated in vacuum. The crude mixture was purified by column chromatography (EtOAc in PE, 0% to 30%) to give 6-chloro-3-(1-methoxy-1-methyl-ethyl)-[1,2,4]triazolo[4,3-a]pyrazine (900 mg, 24.0% yield) as an oil, which was used directly in the next step. LCMS R_(t)=0.779 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₉H₁₂ClN₄0 [M+H]⁺226.9, found 226.9.

II-14: 3-(1-methoxy-1-methyl-ethyl)-6-[6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

To a solution of 6-chloro-3-(1-methoxy-1-methyl-ethyl)-[1,2,4]triazolo[4,3-a]pyrazine (200 mg, 0.88 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (350.0 mg, 1.10 mmol), Cs₂CO₃ (575.0 mg, 1.80 mmol) and Pd(dppf)Cl₂ (32.0 mg, 0.040 mmol) under N₂. After stirring at 90° C. for 16 hours, the mixture was filtered, and the filtrate was concentrated in vacuum. The residue was purified by prep-HPLC (Phenommenex Gemini-NX 80×40 mm, 3 m; A=water (0.05% NH₃·H₂O) B=ACN; 37-69% B) to give 3-(1-methoxy-1-methyl-ethyl)-6-[6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (24.88 mg, 7.10% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.43 (d, 1H), 8.70-8.65 (m, 2H), 8.20-8.13 (m, 1H), 6.92 (d, 1H), 3.14 (s, 3H), 1.86 (s, 6H), 1.84 (s, 6H). ¹⁹F NMR (376.5 MHz CDCl₃)δ_(F)=83.846. LCMS R_(t)=2.351 min in 3 min chromatography, 30-90AB, MS ESI calcd. for C₁₈H₂₁F₃N₅O₂[M+H]+ 396.2, found 396.2.

Example II-16. Synthesis of Compound 11-15: 3-(2-ethoxypropan-2-yl)-6-(6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

Compound II-15: 3-(2-ethoxypropan-2-yl)-6-(6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

To a mixture of 6-chloro-3-(1-ethoxy-1-methyl-ethyl)-[1,2,4]triazolo[4,3-a]pyrazine (70.0 mg, 0.29 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (111.7 mg, 0.34 mmol) and Cs₂CO₃ (189.5 mg, 0.58 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was added Pd(dppf)Cl₂ (21.3 mg, 0.03 mmol) under N₂.

The mixture was stirred at 90° C. for 16 hours. The mixture was filtered, and the filtrate was concentrated to remove dioxane. The aqueous layer was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude mixture was purified by prep-HPLC [Phenomenex Gemini-NX 80×30 mm, 3 μm, water (10 mM NH₄HCO₃)) and B=CH₃CN; 53-83% B over 9.0 minutes)] to give the product ((8.0 mg, 0.02 mmol, 16% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)^(6H)=9.51-9.40 (m, 1H), 8.76 (s, 1H), 8.68 (s, 1H), 8.16 (br d, 1H), 6.92 (d, 1H), 3.27 (d, 2H), 1.85 (br s, 12H), 1.23-1.15 (m, 3H) ¹⁹F NMR (376.5 MHz, CDCl₃)δ_(F)=−83.839. LCMS R_(t) =2.581 min in 4.0 min chromatography, 30-90AB, MS ESI calcd. for C₁₉H₂₃F₃N₅O₂ [M+H]+ 410.2, found 410.2.

Example II-17. Synthesis of Compound 11-16: 6-(5-fluoro-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-3-(1-methoxycyclopropyl)-[1,2,4]triazolo[4,3-a]pyrazine

II-A33: N′-(5-(5-fluoro-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)pyrazin-2-yl)-1-methoxycyclopropanecarbohydrazide

To a mixture of N′-(5-chloropyrazin-2-yl)-1-methoxy-cyclopropanecarbohydrazide (200.0 mg, 0.82 mmol) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (316.5 mg, 0.91 mmol) and Cs₂CO₃ (537.1 mg, 1.65 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was added Pd(dppf)Cl₂ (60.3 mg, 0.08 mmol) under N₂. The mixture was stirred at 90° C. for 16 h. The mixture was filtered and the filtrated was concentrated to remove dioxane. The aqueous layer was extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give the product (250 mg, 0.58 mmol, 70.6% yield) as an oil. LCMS R_(t)=0.972 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₈H₂₀F₄N₅O₃[M+H]+ 430.1, found 430.1.

Compound II-16: 6-(5-fluoro-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-3-(1-methoxycyclopropyl)-[1,2,4]triazolo[4,3-a]pyrazine

To a mixture of N′-[5-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]pyrazin-2-yl]-1-methoxy-cyclopropanecarbohydrazide (0.15 g, 0.35 mmol) in acetic acid (5 mL) was stirred at 120° C. for 16 h to give a solution. Water (10 mL) was added to the solution and the mixture was extracted with EtOAc (15 mL×2). The combined organic phase was washed with saturated NaHCO₃ aqueous (10 mL), brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give the crude product, which was purified by pre-HPLC (Column: Phenomenex Gemini-NX 80×40 mm×3 um; Condition: Water (0.05% NH₃H₂O)-ACN; Begin B: 40, End B: 70) to give the product (10 mg, 0.03 mmol, 6.2% yield) as an oil. 1H NMR (CDCl₃, 400 MHz)δ_(H)=9.44 (s, 1H), 8.68 (s, 1H), 8.54 (s, 1H), 8.03 (br d, H), 3.29 (s, 3H), 1.87 (s, 6H), 1.45 (s, 4H) ¹⁹F NMR (376.5 MHz, CDCl₃)δ_(F)-83.675,-135.098. LCMS R_(t) =2.239 min in 3 min chromatography, 10-80AB, MS ESI calcd. for C₁₈ H₁₈F₄N₅O₂ [M+H]+ 412.2, found 412.2.

Example III-1. Syntheses of Compound III-1: 6-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine & Compound I11-2: 6-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine

III-A2: 1-chloro-2-cyclopropyl-4-(trifluoromethoxy)benzene

A mixture of 2-bromo-1-chloro-4-(trifluoromethoxy)benzene (3 g, 10.89 mmol), cyclopropylboronic acid (982.34 mg, 11.44 mmol), K₃PO₄ (8.09 g, 38.12 mmol), PCy₃ (610.85 mg, 2.18 mmol) and Pd(OAc)₂ (244.52 mg, 1.09 mmol) in toluene (50 mL) and water (5 mL) was stirred at 80° C. under N₂ for 16 hours. After cooling to room temperature, water (50 mL) was added, and the mixture was filtered through Celite. The filtrate was extracted with EtOAc (50 mL×2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash column chromatography (EtOAc in PE=0% to 2%) to give the product (2.57 g, 10.86 mmol, 99% yield) as an oil. 1H NMR (400 MHz, CDCl₃)^(6H)=7.36 (d, 1H), 7.01-6.95 (m, 1H), 6.78 (d, 1H), 2.21 (tt, 1H), 1.13-1.04 (m, 2H), 0.73-0.67 (m, 2H).

III-A3: 2-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of 1-chloro-2-cyclopropyl-4-(trifluoromethoxy)benzene (2.57 g, 10.86 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.31 g, 13.03 mmol), KOAc (2.13 g, 21.72 mmol), X-phos (1.04 g, 2.17 mmol) and Pd₂(dba)₃ (0.99 g, 1.09 mmol) in 1,4-dioxane (50 mL) was stirred at 80° C. under N₂ for 16 hours. After cooling to room temperature, water (50 mL) was added, and the mixture was filtered through Celite. The filtrate was extracted with EtOAc (80 mL×2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (EtOAc in PE=0% to 2%) to give the product (2.5 g, 7.62 mmol, 70% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=7.77 (d, 1H), 6.98-6.96 (m, 1H), 6.64 (s, 1H), 2.75-2.68 (m, 1H), 1.36 (s, 12H), 1.04-1.00 (m, 2H), 0.70-0.66 (m, 2H).

III-A4: 2-chloro-5-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]pyrazine

A mixture of 2-bromo-5-chloro-pyrazine (1.35 g, 6.98 mmol), 2-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.5 g, 7.62 mmol), Cs₂CO₃ (4.55 g, 13.96 mmol) and Pd(dppf)Cl₂ (766.01 mg, 1.05 mmol) in 1,4-dioxane (20 mL) and water (1.5 mL) was stirred at 55° C. under N₂ for 16 hours. After cooling to room temperature, water (20 mL) was added, and the mixture was filtered through Celite. The filtrate was extracted with EtOAc (50 mL×2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (EtOAc in PE=0% to 2% to 5%) to give the product (1.9 g, 4.64 mmol, 66% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.70 (d, 1H), 8.65 (d, 1H), 7.48 (d, 1H), 7.17-7.14 (m, 1H), 6.94-6.90 (m, 1H), 2.05-2.00 (m, 1H), 0.99-0.93 (m, 2H), 0.72-0.67 (m, 2H).

III-A5: [5-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine

A solution of 2-chloro-5-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]pyrazine (1.9 g, 4.64 mmol) and hydrazine hydrate (2.33 g, 46.45 mmol) in MeCN (20 mL) was stirred at 100° C. for 16 hours. After cooling to room temperature, water (50 mL) was added, and the mixture was extracted with EtOAc (50 mL×2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (EtOAc in PE=30% to 50% to 80%) to give the product (1.44 g, 4.64 mmol, 99% yield) as an oil. ¹H NMR (400 MHz, DMSO-d₆)δ_(H)=8.23-8.18 (m, 2H), 8.11 (s, 1H), 7.47 (d, 1H), 7.21 (d, 1H), 6.93 (s, 1H), 4.33 (brs, 2H), 2.17-2.06 (m, 1H), 0.92-0.85 (m, 2H), 0.70-0.63 (m, 2H).

Compound III-1: 6-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine

A mixture of [5-[4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine (200 mg, 0.74 mmol) and (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (171 mg, 0.81 mmol) in toluene (5 mL) was stirred at 110° C. for 96 hours. After cooling to room temperature, the reaction mixture was diluted with water (20 mL). The mixture was extracted with EtOAc (20 mL×2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by pre-HPLC [Welch Xtimate C₁₈ (150 mm×25 mm, 5 mm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 50-80% B over 8 minutes)] to give the product (30.35 mg, 0.078 mmol, 11% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.61 (d, 1H), 8.41 (s, 1H), 7.58 (d, 1H), 7.25-7.18 (m, 1H), 6.97 (s, 1H), 2.10-2.00 (m, 1H), 1.05-0.95 (m, 2H), 0.82-0.72 (m, 2H). LCMS R_(t)=1.01 min in 1.5 min chromatography, 5-95AB

III-A6: 2-bromo-N′-[5-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]-2,2-difluoro-acetohydrazide

To a solution of 2-bromo-2,2-difluoro-acetic acid (0.51 g, 2.9 mmol) in THE (5 mL) was added one drop of DMF and (COCI)₂ (0.29 mL, 3.48 mmol). The resulting mixture was stirred at 20° C. for 1 hour. Then a solution of [5-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine (600 mg, 1.93 mmol) in THE (5 mL) was added to the above mixture. The resulting mixture was stirred at 20° C. for 1 hour. Water (20 mL) was added and the aqueous layer was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give the crude product (0.9 g, 1.93 mmol) as an oil, which was used directly for the next step without further purification. LCMS R_(t) =0.96 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₆H₁₃BrF₅N₄O₂ [M+H]⁺466.9, found 466.9.

III-A7: 3-[bromo(difluoro)methyl]-6-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine

A mixture of 2-bromo-N′-[5-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]-2,2-difluoro-acetohydrazide (0.9 g, 1.93 mmol) and TsOH (99.52 mg, 0.58 mmol) in toluene (10 mL) was stirred at 110° C. for 16 hours. After cooling to room temperature, water (20 mL) was added, and the aqueous layer was extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (EtOAc in PE=0% to 20%) to give the product (140 mg, 0.31 mmol, 16% yield) as an oil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=9.61 (s, 1H), 8.58 (d, 1H), 7.59 (d, 1H), 7.20-7.15 (m, 1H), 6.92 (s, 1H), 2.10-2.00 (m, 1H), 1.05-0.92 (m, 2H), 0.82-0.70 (m, 2H). LCMS R_(t)=1.01 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₆H₁₁BrF₅N₄O[M+H]⁺448.9, found 448.9.

Compound III-2: 6-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine

To a solution of 3-[bromo(difluoro)methyl]-6-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (140 mg, 0.31 mmol) in ethanol (5 mL) was added AgBF₄ (120.93 mg, 0.62 mmol). The mixture was stirred at 60° C. for 6 hours. Brine (20 mL) was added, and the mixture was filtered through Celite. The filtrate was separated, and the aqueous phase was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by prep-HPLC [Welch Xtimate C₁₈ (150 mm×25 mm, 5 mm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 60-80% B over 8 minutes)] to afford the product (32.74 mg, 0.079 mmol, 25% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.52 (d, 1H), 8.45 (s, 1H), 7.57 (d, 1H), 7.22-7.15 (m, 1H), 6.95 (s, 1H), 4.33 (q, 2H), 2.12-1.98 (m, 1H), 1.46 (t, 3H), 1.05-0.95 (m, 2H), 0.82-0.72 (m, 2H). LCMS R_(t)=1.46 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₈H₁₆F₅N₄O₂[M+H]⁺414.9, found 415.2.

Example III-2. Syntheses of Compound III-3: 3-[difluoro(methoxy)methyl]-6-[4-[(1S)-2,2-difluorocyclopropyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine & Compound III-4: 3-[difluoro(methoxy)methyl]-6-[4-[(1R)-2,2-difluorocyclopropyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine. Note stereochemistry is randomly assigned

III-A9: bromo-4-(2,2-difluorocyclopropyl)benzene

A mixture of 1-bromo-4-vinyl-benzene (4.5 g, 24.58 mmol), [bromo(difluoro)methyl]-trimethyl-silane (6.0 g, 29.50 mmol) and TBAB (237.7 mg, 0.74 mmol) in toluene (20 mL) was stirred at 110° C. for 6 hours. After cooling to room temperature, the mixture was diluted with H₂O (30 mL), and the aqueous layer was extracted with EtOAc (30 mL×2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (PE) to give the product (4.6 g, 19.74 mmol, 80% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=7.46 (dd, 2H), 7.10 (d, 2H), 2.75-2.65 (m, 1H), 1.92-1.78 (m, 1H), 1.65-1.55 (m, 1H).

III-A10: 2-[4-(2,2-difluorocyclopropyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a mixture of 1-bromo-4-(2,2-difluorocyclopropyl)benzene (2.0 g, 8.58 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.4 g, 9.44 mmol), KOAc (1.7 g, 17.16 mmol) in 1,4-dioxane (20 mL) was added Pd(dppf)Cl₂ (628 mg, 0.86 mmol). The mixture was stirred at 100° C. for 15 hours. Water (20 mL) was added, and the mixture was filtered. The filtrate was concentrated under reduced pressure to remove dioxane. The aqueous layer was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (PE) to afford the product (1.8 g, 6.43 mmol, 75% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)^(6H)=7.85-7.75 (m, 2H), 7.28-7.20 (m, 2H), 2.82-2.72 (m, 1H), 1.86-1.78 (m, 1H), 1.72-1.60 (m, 1H), 1.35 (s, 12H).

III-A11: 2-chloro-5-[4-(2,2-difluorocyclopropyl)phenyl]pyrazine

To a mixture of 2-bromo-5-chloro-pyrazine (1.37 g, 7.07 mmol), 2-[4-(2,2-difluorocyclopropyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.8 g, 6.43 mmol) and Cs₂CO₃ (4.2 g, 12.85 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was added Pd(dppf)Cl₂ (470 mg, 0.64 mmol). The mixture was stirred at 80° C. for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove dioxane. Water (20 mL) was added, and the aqueous layer was extracted with EtOAc (20 mL×3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (EtOAc in PE 0 to ˜5%) to afford the product (840 mg, 3.15 mmol, 49% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.78 (s, 1H), 8.63 (s, 1H), 7.96 (d, 2H), 7.37 (d, 2H), 2.87-2.78 (m, 1H), 1.96-1.80 (m, 1H), 1.75-1.65 (m, 1H).

III-A12: [5-[4-(2,2-difluorocyclopropyl)phenyl]pyrazin-2-yl]hydrazine

To a solution of 2-chloro-5-[4-(2,2-difluorocyclopropyl)phenyl]pyrazine (840 mg, 3.15 mmol) in MeCN (10 mL) was added NH₂NH₂·H₂O (1.57 mL, 31.5 mmol). The mixture was stirred at 80° C. for 10 hours. Water (30 mL) was added and the aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was triturated with PE/EtOAc (20 mL/2 mL) to afford the product (690 mg, 2.63 mmol, 84% yield) as a solid. ¹H NMR (400 MHz, DMSO-d₆)δ_(H)=8.56 (d, 1H), 8.18 (d, 1H), 8.10 (brs, 1H), 7.90 (d, 2H), 7.32 (d, 2H), 4.33 (brs, 2H), 3.10-2.97 (m, 1H), 2.05-1.92 (m, 2H).

III-A13: 2-bromo-N′-[5-[4-(2,2-difluorocyclopropyl)phenyl]pyrazin-2-yl]-2,2-difluoro-acetohydrazide

To a solution of 2-bromo-2,2-difluoro-acetic acid (0.49 g, 2.8 mmol) in THE (5 mL) was added DMF (10 mg, 0.14 mmol) and (COCI)₂ (0.28 mL, 3.36 mmol). The resulting mixture was stirred at 25° C. for 1 hour. A solution of [5-[4-(2,2-difluorocyclopropyl)phenyl]pyrazin-2-yl]hydrazine (490 mg, 1.87 mmol) in THE (2 mL) was added to the above mixture. The mixture was stirred at 25° C. for 2 hours. Water (30 mL) was added, and the aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to afford the product (780 mg, 1.86 mmol) as an oil. LCMS R_(t)=0.85 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for Cl₅H₁₂BrF₄N₄O[M+H]⁺418.9, found 418.9.

III-A14: 3-[bromo(difluoro)methyl]-6-[4-(2,2-difluorocyclopropyl)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine

To a solution of 2-bromo-N′-[5-[4-(2,2-difluorocyclopropyl)phenyl]pyrazin-2-yl]-2,2-difluoro-acetohydrazide (780 mg, 1.86 mmol) in toluene (10 mL) was added TsOH (96 mg, 0.56 mmol). The mixture was stirred at 110° C. for 48 hours. Water (30 mL) was added, and the aqueous layer was extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE 0 to 20%) to afford the product (300 mg, 0.75 mmol, 40% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)^(6H)=9.60 (s, 1H), 8.45 (s, 1H), 7.96 (d, 2H), 7.42 (d, 2H), 2.90-2.80 (m, 1H), 2.00-1.85 (m, 1H), 1.80-1.68 (m, 1H).

III-A15: 6-[4-(2,2-difluorocyclopropyl)phenyl]-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazine

To a solution of 3-[bromo(difluoro)methyl]-6-[4-(2,2-difluorocyclopropyl)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (150 mg, 0.37 mmol) in methanol (3 mL) was added AgBF₄ (145 mg, 0.75 mmol). The mixture was stirred at 60° C. for 2 hours. Brine (20 mL) was added and the suspension was filtered. The filter cake was washed with EtOAc (20 mL×2). The aqueous layer was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE 0˜30%) to afford the product (120 mg, 0.34 mmol, 91% yield) as a solid. LCMS R_(t)=0.91 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₆H₁₃F₄N₄0 [M+H]⁺353.1, found 353.0.

Compounds III-3 & III-4: 3-[difluoro(methoxy)methyl]-6-[4-[(1R)-2,2-difluorocyclopropyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine & 3-[difluoro(methoxy)methyl]-6-[4-[(1S)-2,2-difluorocyclopropyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine

Analytical SFC: (Chiralcel AD-3 150 mm×4.6 mm I.D., 3 μm, Mobile phase: A: CO₂, B: ethanol (0.05% DEA), Gradient: from 5% to 40% of B in 2 min and hold 40% of B for 1.2 min, then 5% of B for 0.8 min. Flow rate: 4 mL/min, Column temperature: 35° C.) showed two peaks at 1.01 min (49.8%) and 1.10 min (50.2%).

6-[4-(2,2-difluorocyclopropyl)phenyl]-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (120 mg, 0.34 mmol) was purified by SFC (DAICEL CHIRALCEL AD-H (250 mm×30 mm, 5 mm); A=CO₂ and B=EtOH (0.1% NH₃·H₂O); 35° C.; 60 mL/min; 20% B; 8 min run; 70 injections) to give enantiomer 1, randomly assigned as 3-[difluoro(methoxy)methyl]-6-[4-[(1R)-2,2-difluorocyclopropyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (30.23 mg, 0.086 mmol, 25% yield) (R_(t) of Peak 1=1.01 min) as a solid and the enantiomer 2, randomly assigned as 3-[difluoro(methoxy)methyl]-6-[4-[(1S)-2,2-difluorocyclopropyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (31.16 mg, 0.088 mmol, 26% yield) (R_(t) of peak 2=1.10 min) as a solid. The stereochemistry of the compounds were randomly assigned.

Compound III-3:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.52 (d, 1H), 8.46 (d, 1H), 7.93 (d, 2H), 7.40 (d, 2H), 3.97 (s, 3H), 2.90-2.77 (m, 1H), 1.97-1.82 (m, 1H), 1.77-1.67 (m, 1H). LCMS R_(t) =1.35 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₆H₁₃F₄N₄0 [M+H]⁺353.1, found 353.2. Compound III-4:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.52 (d, 1H), 8.46 (s, 1H), 7.93 (d, 2H), 7.40 (d, 2H), 3.97 (s, 3H), 2.90-2.77 (m, 1H), 1.97-1.82 (m, 1H), 1.77-1.67 (m, 1H). LCMS R_(t)=1.35 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₆H₁₃F₄N₄0 [M+H]⁺353.1, found 353.2.

Example III-3. Synthesis of Compound III-5: 3-[ethoxy(difluoro)methyl]-6-[2-methyl-4-(2,2,2-trifluoroethoxymethyl)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine

III-A17: 4-bromo-3-methyl-benzaldehyde

To a solution of 4-bromo-3-methyl-benzaldehyde (10 g, 50.24 mmol) in THE (150 mL) was added NaBH₄ (4.77 g, 125.6 mmol) in portions. The mixture was stirred at 20° C. for 2 hours. 0.5N HCl aqueous (300 mL) was added to the mixture slowly, and the mixture was extracted with EtOAc (500 mL×2). The combined organic phase was washed with brine (500 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give the crude product (10 g, 50.24 mmol) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=7.50 (d, 1H), 7.22 (s, 1H), 7.03 (dd, 1H), 4.60 (s, 2H), 2.40 (s, 3H).

III-A18: 1-bromo-2-methyl-4-(2,2,2-trifluoroethoxymethyl)benzene

To a solution of (4-bromo-3-methyl-phenyl)methanol (5 g, 24.87 mmol) in toluene (200 mL) were added 1,1-(azodicarbonyl)dipiperidine (9.41 g, 37.3 mmol) and tributylphosphine (7.55 g, 37.3 mmol) under N₂. The mixture was stirred at 25° C. for 15 minutes. Then 2,2,2-trifluoroethanol (4.98 g, 49.74 mmol) was added to the mixture, and the mixture was stirred at 25° C. for 16 hours. The mixture was filtered through Celite. The filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (DCM in PE=0% to 5% to 10%, UV=220 nm) to give the product (2.66 g, 9.39 mmol, 37% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=7.54 (d, 1H), 7.23 (d, 1H), 7.04 (dd, 1H), 4.61 (s, 2H), 3.83 (q, 2H), 2.42 (s, 3H).

III-A19: 4,4,5,5-tetramethyl-2-[2-methyl-4-(2,2,2-trifluoroethoxymethyl)phenyl]-1,3,2-dioxaborolane A mixture of 1-bromo-2-methyl-4-(2,2,2-trifluoroethoxymethyl)benzene (3.85 g, 13.6 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.14 g, 16.32 mmol), KOAc (2.67 g, 27.2 mmol) and Pd(dppf)Cl₂ (1.49 g, 2.04 mmol) in 1,4-dioxane (50 mL) was stirred at 90° C. under N₂ for 16 hours. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated. The crude product was purified by flash chromatography on silica gel (DCM in PE=0% to 5% to 10%) to give the product (3.87 g, 11.72 mmol, 86% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=7.78 (d, 1H), 7.17-7.11 (m, 2H), 4.66 (s, 2H), 3.85-3.73 (m, 2H), 2.56 (s, 3H), 1.36 (s, 12H).

III-A21: 3-[chloro(difluoro)methyl]-6-[2-methyl-4-(2,2,2-trifluoroethoxymethyl)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine

A mixture of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (200 mg, 0.84 mmol), 4,4,5,5-tetramethyl-2-[2-methyl-4-(2,2,2-trifluoroethoxymethyl)phenyl]-1,3,2-dioxaborolane (304 mg, 0.92 mmol), Cs₂CO₃ (545 mg, 1.67 mmol) and then Pd(dppf)Cl₂ (92 mg, 0.13 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was stirred at 90° C. for 3 hours. After cooling to room temperature, water (30 mL) and EtOAc (30 mL) were added to the mixture, and the mixture was filtered through Celite. After separation, the organic phase was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 15% to 30%) to give the product (160 mg, 393.4 μmol, 47% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.58 (s, 1H), 8.21 (s, 1H), 7.47 (d, 1H), 7.38-7.31 (m, 2H), 4.74 (s, 2H), 3.89 (q, 2H), 2.45 (s, 3H). LCMS R_(t)=0.89 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₆H₁₃C₁F₅N₄O[M+H]⁺407.1, found 406.9.

Compound III-5: 3-[ethoxy(difluoro)methyl]-6-[2-methyl-4-(2,2,2-trifluoroethoxymethyl)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine

To a solution of 3-[chloro(difluoro)methyl]-6-[2-methyl-4-(2,2,2-trifluoroethoxymethyl)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (160 mg, 0.39 mmol) in MeCN (5 mL) were added Cs₂CO₃ (769 mg, 2.36 mmol) and EtOH (181 mg, 3.93 mmol). The mixture was stirred at 25° C. for 0.5 hours. Water (50 mL) was added to the mixture, and the mixture was extracted with EtOAc (50 mL×2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 30% to 50%) to give the product (53.22 mg, 123.6 μmol, 31% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.52 (s, 1H), 8.24 (s, 1H), 7.47 (d, 1H), 7.36-7.31 (m, 2H), 4.74 (s, 2H), 4.33 (q, 2H), 3.89 (q, 2H), 2.44 (s, 3H), 1.47 (t, 3H). LCMS R_(t)=1.39 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₈ H₁₈F₅N₄O₂ [M+H]⁺417.1, found 417.3.

Example III-4. Synthesis of Compound III-6: 3-[difluoro(methoxy)methyl]-6-[2-methyl-4-(2,2,2-trifluoroethoxymethyl)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine

To a solution of 3-[chloro(difluoro)methyl]-6-[2-methyl-4-(2,2,2-trifluoroethoxymethyl)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (80 mg, 0.20 mmol) in MeCN (3 mL) were added Cs₂CO₃ (384.48 mg, 1.18 mmol) and MeOH (90.67 mg, 1.97 mmol). The mixture was stirred at 25° C. for 0.5 hour. Water (50 mL) was added, and the mixture was extracted with EtOAc (50 mL×2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 30% to 50%) to give the product (37.69 mg, 91.7 μmol, 46% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)^(6H)=9.51 (s, 1H), 8.22 (s, 1H), 7.46 (d, 1H), 7.38-7.30 (m, 2H), 4.74 (s, 2H), 3.96-3.85 (m, 5H), 2.43 (s, 3H). LCMS R_(t)=1.15 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₇H₁₆F₅N₄O₂[M+H]⁺403.1, found 403.1.

Example III-5. Syntheses of Compound I11-7: 6-[4-[(1R)-2,2-difluorocyclopropyl]-2-methyl-phenyl]-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazine & Compound III-8: 6-[4-[(1S)-2,2-difluorocyclopropyl]-2-methyl-phenyl]-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazine. Note stereochemistry is randomly assigned

III-A22: 1-bromo-2-methyl-4-vinyl-benzene

To a suspension of methyl(triphenyl)phosphonium bromide (14.36 g, 40.19 mmol) in THF (150 mL) was added n-BuLi (16.08 mL, 40.19 mmol, 2.5 M in hexane) dropwise under N₂ at 0° C. The mixture was stirred at 0° C. for 1.5 hours. Then 4-bromo-3-methyl-benzaldehyde (5 g, 25.12 mmol) in THF (10 mL) was added to the above mixture dropwise at −20° C. and stirred at 0° C. for 2 hours. The mixture was poured into water (300 mL) and the aqueous layer was extracted with EtOAc (300 mL×2). The combined organic phase was washed with brine (300 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 5% to 10%) to give the product (2 g, 10.15 mmol, 40% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=7.48 (d, 1H), 7.27 (s, 1H), 7.11 (dd, 1H), 6.64 (dd, 1H), 5.75 (d, 1H), 5.27 (d, 1H), 2.41 (s, 3H).

III-A23: 1-bromo-4-(2,2-difluorocyclopropyl)-2-methyl-benzene

A mixture of 1-bromo-2-methyl-4-vinyl-benzene (2 g, 10.15 mmol), [bromo(difluoro)methyl]-trimethyl-silane (2.47 g, 12.18 mmol) and TBAB (98.15 mg, 0.30 mmol) in toluene (20 mL) was stirred at 110° C. for 6 hours. After cooling to room temperature, the mixture was diluted with H₂O (50 mL) and extracted with EtOAc (50 mL×2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (PE) to give the product (2.4 g, 9.71 mmol, 95% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)^(6H)=7.49 (d, 1H), 7.11 (d, 1H), 6.92 (dd, 1H), 2.72-2.64 (m, 1H), 2.40 (s, 3H), 1.87-1.78 (m, 1H), 1.65-1.58 (m, 1H).

III-A24: 2-[4-(2,2-difluorocyclopropyl)-2-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of 1-bromo-4-(2,2-difluorocyclopropyl)-2-methyl-benzene (1.91 g, 7.73 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.35 g, 9.28 mmol), KOAc (1.52 g, 15.46 mmol) and Pd(dppf)Cl₂ (848.44 mg, 1.16 mmol) in 1,4-dioxane (30 mL) was stirred at 90° C. under N₂ for 16 hours. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated. The crude product was purified by flash chromatography on silica gel (DCM in PE=0% to 50% to 100%) to give the product (1.19 g, 4.05 mmol, 52% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=7.74 (d, 1H), 7.05-7.00 (m, 2H), 2.76-2.68 (m, 1H), 2.54 (s, 3H), 1.85-1.76 (m, 1H), 1.70-1.62 (m, 1H), 1.35 (s, 12H).

III-A25: 3-[chloro(difluoro)methyl]-6-[4-(2,2-difluorocyclopropyl)-2-methyl-phenyl]-[1,2,4]triazolo[4,3-a]pyrazine

A mixture of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (900 mg, 3.77 mmol), 2-[4-(2,2-difluorocyclopropyl)-2-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.19 g, 4.05 mmol), Cs₂CO₃ (2.45 g, 7.53 mmol) and then Pd(dppf)Cl₂ (413.29 mg, 0.56 mmol) in 1,4-dioxane (50 mL) and water (5 mL) was stirred at 90° C. under N₂ for 3 hours. After cooling to room temperature, the mixture was filtered through Celite. The cake was washed with EtOAc (50 mL×2). The combined filtrate was washed with brine (50 mL×2), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 20% to 40%) to give the product (320 mg, 863.2 μmol, 22% yield) as an oil. LCMS R_(t)=1.18 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₆H₁₂ClF₄N₄ [M+H]⁺371.1, found 371.0.

III-A26: 6-[4-(2,2-difluorocyclopropyl)-2-methyl-phenyl]-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazine

A mixture of 3-[chloro(difluoro)methyl]-6-[4-(2,2-difluorocyclopropyl)-2-methyl-phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (320 mg, 0.86 mmol), MeOH (397.92 mg, 8.63 mmol), Cs₂CO₃ (1.68 g, 5.18 mmol) in MeCN (10 mL) was stirred at 25° C. for 0.5 hour. Water (50 mL) was added, and the mixture was extracted with EtOAc (50 mL×2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 30% to 50%) to give the product (140 mg, 382.2 μmol, 44% yield) as an oil. LCMS R_(t)=0.96 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₇H₁₅F₄N₄0 [M+H]⁺367.1, found 367.0.

Compounds III-7 & III-8: 6-[4-[(1R)-2,2-difluorocyclopropyl]-2-methyl-phenyl]-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazine & 6-[4-[(1S)-2,2-difluorocyclopropyl]-2-methyl-phenyl]-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazine

Analytical SFC: (Chiralpak AD-3 150×4.6 mm ID, 3 μm. Mobile phase: A: CO₂, B: ethanol (0.05% DEA). Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 5.5 min. Flow rate: 2.5 mL/min Column temperature: 35° C. ABPR: 1500 psi) showed two peaks at 2.97 min (49.68%) and 3.45 min (50.32%). 6-[4-(2,2-difluorocyclopropyl)-2-methyl-phenyl]-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (140 mg, 0.38 mmol) was separated by SFC (DAICEL CHIRALPAK AD-H (250 mm×30 mm, 5 μm); A: CO₂, B=0.1% NH₃H₂O EtOH; 38° C.; 60 mL/min; 25% B; 60 injections) to give the enantiomer 1, randomly assigned as 6-[4-[(1R)-2,2-difluorocyclopropyl]-2-methyl-phenyl]-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (42.63 mg, 114.3 μmol, 29% yield) (R_(t) of Peak 1=2.97 min) as a solid and the enantiomer 2, randomly assigned as 6-[4-[(1S)-2,2-difluorocyclopropyl]-2-methyl-phenyl]-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (44.46 mg, 117.9 μmol, 30% yield) (R_(t) of Peak 2=3.45 min) as a solid. The stereochemistry of the compounds were randomly assigned.

Compound III-7:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.51 (d, 1H), 8.22 (d, 1H), 7.41 (d, 1H), 7.23 (s, 1H), 7.23-7.18 (m, 1H), 3.94 (s, 3H), 2.85-2.76 (m, 1H), 2.41 (s, 3H), 1.93-1.84 (m, 1H), 1.74-1.66 (m, 1H). LCMS R_(t)=1.20 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₇H₁₅F₄N₄0 [M+H]⁺367.1, found 367.2. Compound III-8:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.51 (d, 1H), 8.22 (s, 1H), 7.42 (d, 1H), 7.23 (s, 1H), 7.22-7.18 (m, 1H), 3.93 (s, 3H), 2.85-2.76 (m, 1H), 2.41 (s, 3H), 1.94-1.85 (m, 1H), 1.74-1.66 (m, 1H). LCMS R_(t)=1.14 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₇H₁₅F₄N₄0 [M+H]⁺367.1, found 367.1.

Example III-6. Synthesis of Compound III-9: 3-[ethoxy(difluoro)methyl]-6-[2-methyl-4-[(1R)-1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine & Compound III-10: 3-[ethoxy(difluoro)methyl]-6-[2-methyl-4-[(1S)-1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine

III-A27: 1-(4-bromo-3-methyl-phenyl)ethanol

To a solution of 4-bromo-3-methyl-benzaldehyde (5 g, 25.12 mmol) in THF (100 mL) was added MeMgBr (10.05 mL, 30.14 mmol, 3 M in ethyl ether) dropwise at 0° C. The mixture was stirred at 25° C. for 15 hours. After cooling to room temperature, the mixture was added to the saturated NH₄Cl solution (250 mL). The mixture was extracted with EtOAc (150 mL×3). The combined organic phase was washed with brine (250 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the product (5.3 g, 24.64 mmol) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=7.49 (d, 1H), 7.25 (d, 1H), 7.05 (dd, 1H), 4.84 (q, 1H), 2.41 (s, 3H), 1.47 (d, 3H).

III-A28: 1-bromo-2-methyl-4-[1-(2,2,2-trifluoroethoxy)ethyl]benzene

To a solution of 1-(4-bromo-3-methyl-phenyl) ethanol (5.3 g, 24.64 mmol) in toluene (300 mL) were added tributylphosphine (7.48 g, 36.96 mmol) and 1,1-(azodicarbonyl) dipiperidine (9.33 g, 36.96 mmol) under N₂ at 30° C. The mixture was stirred at 30° C. for 15 minutes. 2,2,2-trifluoroethanol (4.93 g, 49.3 mmol) was added to the mixture. The mixture was stirred at 30° C. under N₂ for 20 hours. After cooling to room temperature, the mixture was filtered through Celite and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (PE) to give the product (3 g, 10.1 mmol, 41% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=7.53 (d, 1H), 7.18 (s, 1H), 7.01 (dd, 1H), 4.51 (q, 1H), 3.71-3.61 (m, 2H), 2.42 (s, 3H), 1.48 (d, 3H).

III-A29: 4,4,5,5-tetramethyl-2-[2-methyl-4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-1,3,2-dioxaborolane

To a mixture of 1-bromo-2-methyl-4-[1-(2,2,2-trifluoroethoxy)ethyl]benzene (3 g, 10.1 mmol) in 1,4-dioxane (30 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.08 g, 12.12 mmol) and KOAc (1.98 g, 20.19 mmol). Pd(dppf)Cl₂ (0.74 g, 1.01 mmol) was added, and the mixture was stirred at 90° C. under N₂ for 3 hours. After cooling to room temperature, the mixture was filtered through Celite. The filtrate was concentrated, and the crude product was purified by flash chromatography on silica gel (PE) to give the product (3.3 g, 9.6 mmol, 95% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=7.83-7.72 (m, 1H), 7.16-7.10 (m, 2H), 4.54 (q, 1H), 3.72-3.57 (m, 2H), 2.56 (s, 3H), 1.49 (d, 3H), 1.35 (s, 12H).

III-A30: 2-chloro-5-[2-methyl-4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]pyrazine

To a mixture of 4,4,5,5-tetramethyl-2-[2-methyl-4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-1,3,2-dioxaborolane (3.3 g, 9.6 mmol) in 1,4-dioxane (30 mL) and water (3 mL) were added Cs₂CO₃ (6.25 g, 19.18 mmol) and 2-bromo-5-chloro-pyrazine (2.23 g, 11.51 mmol). Pd(dppf)Cl₂ (0.7 g, 0.96 mmol) was added, and the mixture was stirred at 55° C. under N₂ for 16 hours. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated. Water (50 mL) was added, and the aqueous layer was extracted with EtOAc (50 mL×2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0 to 10%) to give the product (1.7 g, 5.14 mmol, 54% yield) as an oil. ¹H NMR (400 MHz, DMSO-d⁶)δ_(H)=8.66 (s, 1H), 8.48 (s, 1H), 7.41 (d, 1H), 7.30-7.25 (m, 2H), 4.59 (q, 1H), 3.75-3.60 (m, 2H), 2.40 (s, 3H), 1.51 (d, 3H). LCMS R_(t)=0.96 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₅H₁₅C₁F₃N₂O [M+H]⁺331.1, found 330.9.

III-A31: [5-[2-methyl-4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]pyrazin-2-yl]hydrazine

To a solution of 2-chloro-5-[2-methyl-4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]pyrazine (1.7 g, 5.14 mmol) in MeCN (10 mL) was added hydrazine (1.65 g, 51.4 mmol). The mixture was stirred at 25° C. for 16 hours. After cooling to room temperature, water (20 mL) was added to the mixture, and the aqueous layer was extracted with EtOAc (30 mL×2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=50% to 100%) to afford the product (1.1 g, 3.37 mmol, 66% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.31 (s, 1H), 8.18 (s, 1H), 8.40 (d, 1H), 7.26-7.23 (m, 2H), 6.03 (brs, 1H), 4.59 (q, 1H), 3.77-3.60 (m, 2H), 2.40 (s, 3H), 1.53 (d, 3H). LCMS R_(t)=1.01 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₅Hi₈F₃N₄0 [M+H]⁺327.1, found 327.2.

III-A32: 2-bromo-2,2-difluoro-N′-[5-[2-methyl-4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]pyrazin-2-yl]acetohydrazide

To a solution of 2-bromo-2,2-difluoro-acetic acid (435 mg, 2.49 mmol) in THE (4 mL) were added (COCI)₂ (0.26 mL, 2.98 mmol) and 1 drop of DMF. The mixture was stirred at 25° C. for 1 hour. A solution of [5-[2-methyl-4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]pyrazin-2-yl]hydrazine (540 mg, 1.65 mmol) in THF (2 mL) was added to the above mixture. The mixture was stirred at 28° C. for 1 hour. Water (30 mL) was added, and the aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to afford the product (790 mg, 1.63 mmol) as an oil. LCMS R_(t)=0.90 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for Cl₇H₁₇BrF₅N₄O₂ [M+H]⁺485.0, found 484.8.

III-A33: 3-[bromo(difluoro)methyl]-6-[2-methyl-4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine

To a mixture of 2-bromo-2,2-difluoro-N′-[5-[2-methyl-4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]pyrazin-2-yl]acetohydrazide (790 mg, 1.63 mmol) in toluene (10 mL) was added TsOH (84.46 mg, 0.49 mmol). The mixture was stirred at 125° C. for 15 hours. After cooling to room temperature, water (20 mL) was added, and the aqueous layer was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 15% to 20%) to give the product (180 mg, 0.39 mmol, 24% yield) as an oil. LCMS R_(t)=1.23 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₇H₁₅BrF₅N₄O[M+H]⁺467.0, found 466.9.

III-A34: 3-[ethoxy(difluoro)methyl]-6-[2-methyl-4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine

To a solution of 3-[bromo(difluoro)methyl]-6-[2-methyl-4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (180 mg, 0.39 mmol) in ethanol (3 mL) were added AgBF₄ (225.18 mg, 1.16 mmol) and Na₂CO₃ (123.03 mg, 1.16 mmol). The mixture was stirred at 70° C. for 2.5 hours. Brine (40 mL) was added, and the aqueous layer was filtered through Celite. The filter cake was eluted with EtOAc (10×3 mL). The filtrate was separated, and the aqueous layer was extracted with EtOAc (20×3 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0˜20%) to afford the product (70 mg, 0.16 mmol, 42% yield) as an oil. LCMS R_(t)=0.93 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₉H₂₀F₅N₄O₂[M+H]⁺431.1, found 431.0.

Compounds III-9 & III-10: 3-[ethoxy(difluoro)methyl]-6-[2-methyl-4-[(1R)-1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine & 3-[ethoxy(difluoro)methyl]-6-[2-methyl-4-[(1S)-1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine

Analytical SFC: (Chiralcel AD-3 150×4.6 mm ID, 3 μm. Mobile phase: A: CO₂ B: ethanol (0.05% DEA). Gradient: from 5% to 40% of B in 5 min and from 40% to 5% of B in 0.5 min and hold 5% of B for 1.5 min. Flow rate: 2.5 mL/min. Column temperature: 35° C. ABPR: 1500 psi) showed two peaks at 2.02 min (49.82%) and 2.20 min (50.18%). 3-[ethoxy(difluoro)methyl]-6-[2-methyl-4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (70 mg, 0.16 mmol) was purified by SFC (DAICEL CHIRALCEL AD-H (250 mm×30 mm, 5 μm) A=CO₂ and B=0.1% NH₃H₂O-EtOH; 60 mL/min; 25% B, injections: 60) to afford the enantiomer 1, randomly assigned as 3-[ethoxy(difluoro)methyl]-6-[2-methyl-4-[(1R)-1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (24.37 mg, 0.056 mmol, 34% yield) (R_(t) of Peak 1=2.07 min) and the enantiomer 2, randomly assigned as 3-[ethoxy(difluoro)methyl]-6-[2-methyl-4-[(1S)-1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (28.47 mg, 0.064 mmol, 39% yield) (R_(t) of Peak 2=2.24 min) as oils. The stereochemistry of the compounds were randomly assigned.

Compound III-9:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.51 (s, 1H), 8.25 (s, 1H), 7.46 (d, 1H), 7.35-7.27 (m, 2H), 4.63 (q, 1H), 4.33 (q, 2H), 3.76-3.69 (m, 2H), 2.44 (s, 3H), 1.55 (d, 3H), 1.47 (t, 3H). LCMS R_(t)=1.22 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₉H₂₀F₅N₄O₂[M+H]⁺431.1, found 431.2. Compound III-10:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.52 (s, 1H), 8.25 (s, 1H), 7.47 (d, 1H), 7.35-7.27 (m, 2H), 4.63 (q, 1H), 4.33 (q, 2H), 3.78-3.69 (m, 2H), 2.44 (s, 3H), 1.55 (d, 3H), 1.47 (t, 3H). LCMS R_(t)=1.22 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₉H₂₀F₅N₄O₂[M+H]⁺431.1, found 431.1.

Example III-7. Synthesis of Compound III-11: 3-(ethoxydifluoromethyl)-6-(4-((2,2,2-trifluoroethoxy)methyl)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine

III-A37: 1-bromo-4-((2,2,2-trifluoroethoxy)methyl)benzene

To a stirred solution of NaH (300 mg, 7.5 mmol) in DMF (10.0 mL) was added 2,2,2-trifluoroethan-1-ol (500 mg, 5.0 mmol) at 0° C., and the resulting mixture was stirred for 15 minutes. To the reaction mixture was added 1-bromo-4-(bromomethyl)benzene (1.25 g, 5.0 mmol) in DMF (4.0 mL) dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction mixture was cooled to 10° C. and treated with ice water (20 mL). The reaction mixture was extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated to afford 1-bromo-4-((2,2,2-trifluoroethoxy)methyl)benzene (1.15 g). It was used for the next step without further purification.

III-A38: 4,4,5,5-tetramethyl-2-(4-((2,2,2-trifluoroethoxy)methyl)phenyl)-1,3,2-dioxaborolane

To a stirred solution of 1-bromo-4-((2,2,2-trifluoroethoxy)methyl)benzene (1.15 g, 4.2 mmol) and bis(pinacolato)diboron (1.39 g, 5.46 mmol) in 1,4-dioxane (12.0 mL) was added potassium acetate (1.59 g, 16.2 mmol). Pd(dppf)Cl₂.DCM (0.45 g, 0.55 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 85° C. for 4 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with 8% ethyl acetate/PE to afford 4,4,5,5-tetramethyl-2-(4-((2,2,2-trifluoroethoxy)methyl)phenyl)-1,3,2-dioxaborolane (1.18 g, 3.76 mmol, 89% yield) as a liquid. ¹H NMR (400 MHz, CD₃0D)δ_(H)=7.76 (d, 2H), 7.37 (d, 2H), 4.70 (s, 2H), 3.99-3.92 (m, 2H), 1.36 (s, 12H).

III-A39: 3-(chlorodifluoromethyl)-6-(4-((2,2,2-trifluoroethoxy)methyl)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine

To a stirred solution of 6-chloro-3-(chlorodifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine (650 mg, 2.72 mmol) and 4,4,5,5-tetramethyl-2-(4-((2,2,2-trifluoroethoxy)methyl)phenyl)-1,3,2-dioxaborolane (1.12 g, 3.36 mmol) in 1,4-dioxane (9.0 mL) was added water (1.0 mL) and K₂CO₃ (751 mg, 5.44 mmol). Pd(PPh₃)2Cl₂ (190 mg, 0.27 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with 30% ethyl acetate/PE to afford 3-(chlorodifluoromethyl)-6-(4-((2,2,2-trifluoroethoxy)methyl)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine (195 mg, 0.49 mmol, 18% yield). LCMS: 393.0 (M+H), Rt 2.38 min; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min

III-Compound11: 3-(ethoxydifluoromethyl)-6-(4-((2,2,2-trifluoroethoxy)methyl)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine

To a stirred suspension of Cs₂CO₃ (970 mg, 2.98 mmol) in MeCN (2.0 mL) was added ethanol (0.58 mL, 9.93 mmol) at room temperature, and the resulting mixture was stirred for 15 minutes. To the reaction mixture was added 3-(chlorodifluoromethyl)-6-(4-((2,2,2-trifluoroethoxy)methyl)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine (195 mg, 0.49 mmol) in MeCN (10.0 mL) dropwise, and the mixture was stirred for 6 hours. The reaction mixture was treated with water (50 mL) and extracted with ethyl acetate (2×40 mL). The organic layer was washed with brine (30 mL), dried over Na₂SO₄, and concentrated. The crude product was purified by preparative HPLC to afford 11 (30 mg, 0.07 mmol, 14% yield) as a solid. Prep-HPLC method: R_(t) 12.31; Column: X-Bridge C-18 (150×19 mm), 5.0 μm; 0.1% FA in water/acetonitrile; Flow Rate: 15.0 mL/min. HPLC: Rt 5.01 min; Column: X-Bridge C₈ (50×4.6) mm, 3.5 μm; Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 403.1 (M+H), R_(t) 2.53 min, 97.7%; Column: X-Bridge C₈ (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% TFA in water:ACN (95:5), B: 0.1% TFA in ACN; Flow Rate: 1.5 mL/min. ¹H NMR (400 MHz, DMSO-d₆)δ_(H)=9.70 (d, 1H), 8.82 (d, 1H), 8.13 (d, 2H), 7.53 (d, 2H), 4.76 (s, 2H), 4.32 (q, 2H), 4.16 (q, 2H), 1.40 (t, 3H).

Example III-8. Synthesis of Compound I11-12: 6-(4-(1,1-difluoro-2-methoxyethoxy)phenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine

III-A41: 1-bromo-4-(1,1-difluoro-2-methoxyethoxy)benzene

To a stirred solution of 2-(4-bromophenoxy)-2,2-difluoroethan-1-ol (865 mg, 3.44 mmol) in THF (15.0 mL) was added NaH (60% in mineral oil, 0.28 g, 6.88 mmol) in small portions at 0° C. The reaction mixture was stirred for 20 minutes, and iodomethane (0.98 g, 6.88 mmol) in THF (1.0 mL) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled to 10° C., treated with ice water (30 mL), and extracted with ethyl acetate (2×30 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄ and concentrated. The crude product was purified by column chromatography on silica gel with 2% ethyl acetate/PE to afford 1-bromo-4-(1,1-difluoro-2-methoxyethoxy)benzene (860 mg, 3.24 mmol, 94% yield) as an oil. GCMS: 266.0 (M*) and 268.0 (M+2), Rt 2.25 min.

III-A42: 2-(4-(1,1-difluoro-2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a stirred solution of 1-bromo-4-(1,1-difluoro-2-methoxyethoxy)benzene (860 mg, 3.24 mmol) and bis(pinacolato)diboron (1.07 g, 4.21 mmol) in 1,4-dioxane (15.0 mL) was added potassium acetate (636 mg, 6.48 mmol). Pd(dppf)Cl₂.DCM (344 mg, 0.42 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 85° C. for 4 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with 4% ethyl acetate/PE to afford 2-(4-(1,1-difluoro-2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (605 mg, 1.93 mmol, 59% yield) as a liquid. GCMS: 314.1 (M*), Rt 3.77 min

Compound III-12: 6-(4-(1,1-difluoro-2-methoxyethoxy)phenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine

To a stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine (500 mg, 2.24 mmol) and 2-(4-(1,1-difluoro-2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (562 mg, 1.79 mmol) in 1,4-dioxane (6.0 mL) was added water (0.5 mL) and Cs₂CO₃ (1.46 g, 4.49 mmol). Pd(dppf)Cl₂.DCM (183 mg, 0.22 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude reaction mixture was treated with water (30 mL) and extracted with ethyl acetate (2×30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated. The crude product was purified by column chromatography on silica gel with 15% ethyl acetate/PE to afford III-12 (340 mg, 0.9 mmol, 50% yield) as a solid. HPLC: Rt 4.55 min; Column: X-Bridge C₈ (50×4.6) mm, 3.5 μm; Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 375.1 (M+H), Rt 2.25 min, 99.1%; Column: ZORBAX XDB C-18 (50×4.6 mm), 5.0 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min. ¹H NMR (400 MHz, DMSO-d₆)δ_(H)=9.77 (d, 1H), 9.03 (s, 1H), 8.24 (d, 2H), 7.39 (d, 2H), 3.96 (t, 2H), 3.47 (s, 3H).

Example III-9. Synthesis of Compound I11-13: (R)-3-(difluoromethyl)-6-(6-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

To a stirred solution of 6-chloro-3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine (150 mg, 0.73 mmol) and (R)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine (256 mg, 0.81 mmol) in 1,4-dioxane (1.8 mL) was added water (0.2 mL) and Cs₂CO₃ (478 mg, 1.47 mmol). Pd(dppf)Cl₂.DCM (60 mg, 0.07 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude reaction mixture was treated with water (20 mL) and extracted with EtOAc (2×30 mL). The organic layer was washed with brine (20 mL), dried over Na₂SO₄ and concentrated. The crude product was purified by column chromatography on silica gel with 30% EtOAc/PE to afford III-13 (95 mg, 0.25 mmol, 34% yield) as a solid. HPLC: Rt 4.63 min; Column: X-Bridge C₈ (50×4.6) mm, 3.5 μm; Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 360.1 (M+H), Rt 2.34 min, 99.4%; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min. ¹H NMR (400 MHz, DMSO-d₆)δ_(H)=9.69 (d, 1H), 9.23 (d, 1H), 8.93 (d, 1H), 8.49 (dd, 1H), 7.82 (t, 1H), 7.15 (d, 1H), 6.01-5.97 (m, 1H), 1.51 (d, 3H).

Example III-10. Syntheses of Compound I11-14: (R)-6-(6-(1-cyclopropyl-2,2,2-trifluoroethoxy)pyridin-3-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine & Compound III-15: (S)-6-(6-(1-cyclopropyl-2,2,2-trifluoro ethoxy)pyridin-3-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine

To a stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine (345 mg, 1.55 mmol) and 2-(1-cyclopropyl-2,2,2-trifluoroethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (485 mg, 1.41 mmol) in 1,4-dioxane (9.0 mL) was added Cs₂CO₃ (918 mg, 2.82 mmol) and water (1.0 mL). Pd(dppf)Cl₂.DCM (115 mg, 0.14 mmol) was added to the reaction mixture under nitrogen atmosphere, and the mixture was heated at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with 14% ethyl acetate/PE to afford racemic compound. The racemic mixture was separated by SFC purification to afford III-14 (20 mg, 0.05 mmol, 3.5% yield) and III-15 (15 mg, 0.036 mmol, 2.5% yield) as solids. Chiral method: SFC column: Lux C₃; mobile phase: 90:10 (A: B), A=liquid CO₂, B=0.5% isopropyl amine in methanol; flow rate: 3.0 mL/min; wave length: 254 nm. The stereochemistry of III-14 and III-15 was randomly assigned.

Compound III-14: HPLC: Rt 5.38 min; Column: X-Bridge C₈ (50×4.6) mm, 3.5 μm; Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 404.1 (M+H), Rt 2.61 min, 95.1%; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min. Chiral method: Rt 3.35 min, SFC column: Lux C₃; mobile phase: 90:10 (A: B), A=liquid CO₂, B=0.5% isopropyl amine in methanol; flow rate: 3.0 mL/min; wave length: 254 nm. ¹H NMR (400 MHz, CD₃0D)δ_(H)=9.61 (d, 1H), 8.89-8.88 (m, 2H), 8.46 (dd, 1H), 7.04 (dd, 1H), 5.54-5.50 (m, 1H), 1.37-1.26 (m, 1H), 0.80-0.75 (m, 1H), 0.68-0.63 (m, 3H). Compound III-15: HPLC: Rt 5.38 min; Column: X-Bridge C₈ (50×4.6) mm, 3.5 μm; Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 404.0 (M+H), Rt 2.61 min, 98.2%; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min. Chiral method: Rt 3.64 min, SFC column: Lux C₃; mobile phase: 90:10 (A: B), A=liquid CO₂, B═0.5% isopropyl amine in methanol; flow rate: 3.0 mL/min; wave length: 254 nm. ¹H NMR (400 MHz, CD₃0D):δ_(H)=9.61 (d, 1H), 8.89-8.88 (m, 2H), 8.46 (dd, 1H), 7.04 (dd, 1H), 5.55-5.48 (m, 1H), 1.37-1.28 (m, 1H), 0.80-0.75 (m, 1H), 0.68-0.63 (m, 3H).

Example III-11. Synthesis of Compound I11-16: (S)-3-(difluoromethyl)-6-(6-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

To a stirred solution of 6-chloro-3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine (150 mg, 0.73 mmol) and (S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine (245 mg, 0.77 mmol) in 1,4-dioxane (2.8 mL) was added Cs₂CO₃ (477 mg, 1.47 mmol) and water (0.40 mL). Pd(dppf)Cl₂.DCM (60 mg, 0.07 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 90° C. for 3 h. The reaction mixture was cooled to room temperature and filtered through Celite. The crude reaction mixture was treated with water (30 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated. The crude product was purified by column chromatography on silica gel with 30% ethyl acetate/PE to afford III-16 (120 mg, 0.32 mmol, 44% yield) as a solid. HPLC: Rt 4.65 min; Column: X-Bridge C₈ (50×4.6) mm, 3.5 μm; Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 359.8 (M+H), Rt 2.34 min, 98.7%; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min. ¹H NMR (400 MHz, CD₃0D)δ_(H)=9.55 (d, 1H), 8.94-8.90 (m, 2H), 8.44 (dd, 1H), 7.60 (t, 1H), 7.03 (dd, 1H), 5.99-5.92 (m, 1H), 1.54 (d, 3H).

Example III-12. Syntheses of Compound I11-17: 3-[difluoro(methoxy)methyl]-6-[4-[(1R)-1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine; Compound I11-18: 3-[difluoro(methoxy)methyl]-6-[4-[(1S)-1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine; Compound III-19: 3-[ethoxy(difluoro)methyl]-6-[4-[(1R)-1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine; and Compound I1-20: 3-[ethoxy(difluoro)methyl]-6-[4-[(1S)-1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine

III-A47: 1-bromo-4-[1-(2,2,2-trifluoroethoxy)ethyl]benzene

To a solution of 1-(4-bromophenyl)ethanol (10.0 g, 49.74 mmol) in toluene (500 mL) were added tributylphosphine (15.09 g, 74.6 mmol) and 1,1-(azodicarbonyl)dipiperidine (18.82 g, 74.6 mmol) under N₂ at 30° C. The mixture was stirred at 30° C. for 30 min. Then 2,2,2-trifluoroethanol (9.95 g, 99.47 mmol) was added to the mixture. The mixture was stirred at 30° C. for 20 hours under N₂. The mixture was filtered, and the filter cake was washed with toluene (100 mL×2). The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (DCM in PE 0˜1%) to give the product (4.7 g, 16.60 mmol, 33% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=7.51 (d, 2H), 7.21 (d, 2H), 4.55 (q, 1H), 3.72-3.60 (m, 2H), 1.49 (d, 3H).

III-A48: 4,4,5,5-tetramethyl-2-[4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-1,3,2-dioxaborolane

To a mixture of 1-bromo-4-[1-(2,2,2-trifluoroethoxy)ethyl]benzene (4.7 g, 16.60 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.64 g, 18.26 mmol), KOAc (3.26 g, 33.2 mmol) in 1,4-dioxane (50 mL) was stirred at 90° C. for 12 hours under N₂. After cooling to 25° C., the mixture was filtered, and the filtrate was concentrated. Water (50 mL) was added, and the aqueous layer was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (DCM in PE=0˜5%) to afford the product (4.2 g, 12.72 mmol, 77% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=7.83 (d, 2H), 7.33 (d, 2H), 4.59 (q, 1H), 3.72-3.58 (m, 2H), 1.50 (d, 3H), 1.35 (s, 12H).

III-A49: 2-chloro-5-[6-[1-(trifluoromethyl)propoxy]-3-pyridyl]pyrazine

To a solution of 4,4,5,5-tetramethyl-2-[4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-1,3,2-dioxaborolane (4.2 g, 12.72 mmol) in 1,4-dioxane (40 mL) and water (4 mL) were added 2-bromo-5-chloro-pyrazine (2.71 g, 13.99 mmol) and Cs₂CO₃ (8.29 g, 25.44 mmol). Then Pd(dppf)Cl₂ (931 mg, 1.27 mmol) was added to the above mixture. The mixture was stirred at 50° C. for 5 hours. The mixture was filtered, and the filtrate was concentrated. Water (50 mL) was added, and the aqueous layer was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE 0 to 10%) to afford the product (3.4 g, 10.74 mmol, 84% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.80 (s, 1H), 8.65 (s, 1H), 8.01 (d, 2H), 7.48 (d, 2H), 4.65 (q, 1H), 3.78-3.65 (m, 2H), 1.55 (d, 3H).

III-A50: [5-[4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]pyrazin-2-yl]hydrazine

To a solution of 2-chloro-5-[4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]pyrazine (3.4 g, 10.74 mmol) in MeCN (40 mL) was added hydrazine hydrate (5.37 g, 107.35 mmol). The mixture was stirred at 90° C. for 16 hours. Water (100 mL) was added and the aqueous layer was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to afford the product (3.2 g, 10.2 mmol) as a solid. ¹H NMR (400 MHz, DMSO-d₆)δ_(H)=8.56 (s, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 7.94 (d, 2H), 7.39 (d, 2H), 4.68 (q, 1H), 4.34 (brs, 2H), 4.02-3.93 (m, 1H), 3.90-3.77 (m, 1H), 1.43 (d, 3H).

III-A51: 2-bromo-2,2-difluoro-N′-[5-[4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]pyrazin-2-yl]acetohydrazide

To a solution of 2-bromo-2,2-difluoro-acetic acid (1.34 g, 7.69 mmol) in THE (20 mL) were added (COCI)₂ (0.79 mL, 9.22 mmol) and 5 drops of DMF. The mixture was stirred at 30° C. for 1 hour. A solution of [5-[4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]pyrazin-2-yl]hydrazine (1.6 g, 5.12 mmol) in THE (5 mL) was added to the above mixture. The mixture was stirred at 28° C. for 16 hours. Water (30 mL) was added, and the aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to afford the product (2.4 g, 5.12 mmol) as an oil. LCMS R_(t)=1.19 min in 2 min chromatography, 10-80AB, MS ESI calcd. for C₁₆H₁₅BrF₅N₄O₂ [M+H]⁺471.0, found 471.0.

III-A52: 3-[bromo(difluoro)methyl]-6-[4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine

To a solution of 2-bromo-2,2-difluoro-N′-[5-[4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]pyrazin-2-yl]acetohydrazide (2.4 g, 5.12 mmol) in toluene (5 mL) was added TsOH (264 mg, 1.53 mmol). The mixture was stirred at 130° C. for 16 hours. Water (20 mL) was added, and the aqueous layer was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE 0 to 20%) to afford the product (240 mg, 0.53 mmol, 10% yield) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.59 (s, 1H), 8.46 (s, 1H), 8.00 (d, 2H), 7.52 (d, 2H), 4.68 (q, 1H), 3.78-3.68 (m, 2H), 1.54 (d, 3H).

III-A54: 3-[difluoro(methoxy)methyl]-6-[4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine

To a solution of 3-[bromo(difluoro)methyl]-6-[4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (240 mg, 0.53 mmol) in methanol (3 mL) were added AgBF₄ (206.39 mg, 1.06 mmol) and Na₂CO₃ (113 mg, 1.06 mmol). The mixture was stirred at 70° C. for 4 hours. Brine (20 mL) was added, and the mixture was filtered. The aqueous layer was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (EtOAc in PE 0 to 20%) to afford the product (140 mg, 0.35 mmol, 65% yield) as an oil. LCMS R_(t)=0.99 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C₁₇H₁₆F₅N₄O₂[M+H]⁺403.1, found 403.0.

Compounds III-17 & III-18: 3-[difluoro(methoxy)methyl]-6-[4-[(1R)-1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine & 3-[difluoro(methoxy)methyl]-6-[4-[(1S)-1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine

Analytical SFC: (Chiralpak AD-3 50×4.6 mm ID, 3 μm. Mobile phase: A: CO₂, B: ethanol (0.05% DEA). Gradient: from 5% to 40% of B in 2 min and hold 40% of B for 1.2 min, then 5% of B for 0.8 min. Flow rate: 4 mL/min. Column temperature: 35° C. ABPR: 1500 psi) showed two peaks at 0.715 min (49.9%) and 0.795 min (50.1%). 3-[difluoro(methoxy)methyl]-6-[4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (140 mg, 0.35 mmol) was purified by SFC (DAICEL CHIRALCEL AD (250 mm×30 mm, 10 μm) A=CO₂ and B=0.1% NH₃H₂O-EtOH; 60 mL/min; 15% B, injections: 80) to afford the enantiomer 1, randomly assigned as 3-[difluoro(methoxy)methyl]-6-[4-[(1R)-1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (40.95 mg, 0.10 mmol, 29% yield) (R_(t) of Peak 1=0.726 min) and the enantiomer 2, randomly assigned as 3-[difluoro(methoxy)methyl]-6-[4-[(1S)-1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (56 mg, 0.14 mmol, 39% yield) (R_(t) of Peak 2=0.804 min) as solids.

Compound III-17:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.52 (s, 1H), 8.47 (s, 1H), 7.97 (d, 2H), 7.50 (d, 2H), 4.74-4.63 (m, 1H), 3.97 (s, 3H), 3.82-3.63 (m, 2H), 1.55 (d, 3H). LCMS R_(t)=1.29 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₇H₁₆F₅N₄O₂[M+H]⁺403.1, found 403.1. Compound III-18:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.51 (s, 1H), 8.47 (s, 1H), 7.97 (d, 2H), 7.50 (d, 2H), 4.74-4.63 (m, 1H), 3.96 (s, 3H), 3.82-3.63 (m, 2H), 1.55 (d, 3H). LCMS R_(t)=1.29 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₇H₁₆F₅N₄O₂[M+H]⁺403.1, found 403.0. A53: 3-[ethoxy(difluoro)methyl]-6-[4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine Compounds III-19 & III-20: 3-[ethoxy(difluoro)methyl]-6-[4-[(1R)-1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine & 3-[ethoxy(difluoro)methyl]-6-[4-[(1S)-1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine

To a solution of 3-[bromo(difluoro)methyl]-6-[4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (200 mg, 0.44 mmol) in ethanol (3 mL) were added AgBF₄ (258 mg, 1.33 mmol) and Na₂CO₃ (141 mg, 1.33 mmol). The mixture was stirred at 70° C. for 3 hours. Brine (20 mL) was added, and the suspension was filtered. The filtrate was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE 0 to 15%) to afford the product (110 mg, 0.26 mmol, 60% yield) as an oil. LCMS R_(t)=1.24 min in 2 min chromatography, 10-80AB, MS ESI calcd. for C₁₈ H₁₈F₅N₄O₂ [M+H]⁺417.1, found 417.1.

Analytical SFC: (Chiralpak AD-3 50×4.6 mm ID, 3 μm. Mobile phase: A: CO₂, B: ethanol (0.05% DEA). Gradient: from 5% to 40% of B in 2 min and hold 40% of B for 1.2 min, then 5% of B for 0.8 min. Flow rate: 4 mL/min. Column temperature: 35° C. ABPR: 1500 psi) showed two peaks at 0.673 min (50.0%) and 0.740 min (50.0%). 3-[ethoxy(difluoro)methyl]-6-[4-[1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (110 mg, 0.26 mmol) was purified by SFC (DAICEL CHIRALCEL AD-H (250 mm×30 mm, 5 μm) A=CO₂ and B=0.1% NH₃H₂O-EtOH; 60 mL/min; 15% B, injections: 70) to afford the enantiomer 1, randomly assigned as 3-[ethoxy(difluoro)methyl]-6-[4-[(1R)-1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (15.93 mg, 0.038 mmol, 14% yield) (R_(t) of Peak 1=0.661 min) and the enantiomer 2, randomly assigned as 3-[ethoxy(difluoro)methyl]-6-[4-[(1S)-1-(2,2,2-trifluoroethoxy)ethyl]phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (10.94 mg, 0.026 mmol, 10% yield) (R_(t) of Peak 2=0.727 min) as solids.

Compound III-19:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.53 (s, 1H), 8.50 (s, 1H), 7.97 (d, 2H), 7.50 (d, 2H), 4.74-4.63 (m, 1H), 4.37 (q, 2H), 3.82-3.63 (m, 2H), 1.70-1.45 (m, 6H). LCMS R_(t)=1.32 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₈ H₁₈F₅N₄O₂ [M+H]⁺417.1, found 417.0. Compound III-20:¹H NMR (400 MHz, CDCl₃)δ_(H)=9.53 (s, 1H), 8.50 (s, 1H), 7.97 (d, 2H), 7.50 (d, 2H), 4.74-4.63 (m, 1H), 4.37 (q, 2H), 3.82-3.63 (m, 2H), 1.70-1.45 (m, 6H). LCMS R_(t)=1.31 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C₁₈ H₁₈F₅N₄O₂ [M+H]⁺417.1, found 417.0.

Example III-13: Syntheses of Intermediates

Synthesis of III-A20 (6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine):

To a stirred solution of 2-chloro-N′-(5-chloropyrazin-2-yl)-2,2-difluoroacetohydrazide (6.0 mg, 23.34 mmol) in DCM (120 mL) was added trifluoromethanesulfonic anhydride (4.73 mL, 28.01 mmol) and 2-methoxypridine (4.91 mL, 46.69 mmol) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was treated with 10% sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (50 mL), dried over Na₂SO₄ and concentrated. The crude product was purified by column chromatography on silica gel with 15% EtOAc/PE to afford the product (4.0 g, 16.5 mmol, 71% yield) as a solid. LCMS: 239.0 (M+H), Rt 1.66 min Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm Mobile Phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

Synthesis of III-A43 ((R)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine):

To a stirred solution of (R)-5-bromo-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine (3.1 g, 11.5 mmol) and bis(pinacolato)diboron (3.79 g, 14.92 mmol) in 1,4-dioxane (35.0 mL) was added potassium acetate (2.25 g, 22.96 mmol). Pd(dppf)Cl₂.DCM (1.41 g, 1.72 mmol) was added to the reaction mixture under nitrogen atmosphere, and the mixture was heated at 90° C. for 12 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with 6% ethyl acetate/PE to afford (R)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine (2.8 g, 8.83 mmol, 76% yield) as a solid. LCMS: 318.0 (M+H), Rt 4.04 min; Column: ZORBAX Extend (50×4.6 mm), 5 μm; Mobile Phase: A: 10 mM Ammonium acetate in water, B: ACN; Flow Rate: 1.2 mL/min.

Synthesis of III-A44 (2-(1-cyclopropyl-2,2,2-trifluoroethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine):

To a stirred solution of 5-bromo-2-(1-cyclopropyl-2,2,2-trifluoroethoxy)pyridine (3.1 g, 10.47 mmol) and bis(pinacolato)diboron (3.46 g, 13.61 mmol) in 1,4-dioxane (30 mL) was added potassium acetate (1.72 g, 20.94 mmol). Pd(dppf)Cl₂.DCM (0.86 g, 1.05 mmol) was added to the reaction mixture under nitrogen atmosphere, and the mixture was heated at 90° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered through Celite. The reaction mixture was treated with ice water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated. The crude product was purified by column chromatography on silica gel with 4% ethyl acetate/PE to afford 2-(1-cyclopropyl-2,2,2-trifluoroethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.2 g, 9.3 mmol, 89% yield). LCMS: 344.1 (M+H), Rt 3.18 min; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

Synthesis of III-A45 ((S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine):

To a stirred solution of compound (S)-5-bromo-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine (0.5 g, 1.85 mmol) and bis(pinacolato)diboron (0.52 g, 2.04 mmol) in 1,4-dioxane (5.0 mL) was added potassium acetate (0.36 g, 3.7 mmol). Pd(dppf)Cl₂.DCM (0.15 g, 0.19 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 80° C. for 12 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with 10% ethyl acetate/PE to afford compound (S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((1,1,1-trifluoropropan-2-yl)oxy)pyridine (302 mg, 0.95 mmol, 51% yield). LCMS: 318.1 (M+H), Rt 3.04 min; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

Efficacy of Exemplary Compounds in the Modulation of Late Sodium Current (INaL)

Functional characterization of exemplary compounds to modulate INaL expressed by the NaV1.6 voltage-gated sodium channel was accomplished using the PatchXpress™ high throughput electrophysiology platform (Molecular Devices, Sunnyvale, CA). HEK-293 cells expressing recombinant, human NaVI.6 (hNaV1.6) were grown in DMEM/high-glucose Dulbecco's modified, 10% FBS, 2 mM sodium pyruvate, 10 mM HEPES and 400 pg/mL G418. Cells were grown to 50%-80% confluency prior to harvesting. Trypsinized cells were washed, allowed to recover for 1 hour and then resuspended in extracellular recording solution at a concentration of 1×106 cells/ml. The onboard liquid handling facility of the PatchXpress was used for dispensing cells and applying test compounds. NaV late currents were evoked by the application of 300 nM ATX-II. INaL was evoked by depolarizing pulses to 0 mV for 200 ms from a non-inactivating holding potential (e.g., −120 mV) at a frequency of 0.1 Hz. INaL amplitude and stability were determined by analyzing the mean current amplitude over the final 20 ms of the test pulse. Following steady state block with exemplary compounds (e.g., as described herein), a Na+ free solution containing an impermeant cation (e.g., Choline or NDMG) was added to confirm the identity of the sodium current. Percent steady-state inhibition of INaL was calculated as: [(INaL_compound)/(INaL_control)]*100, where INaL_compound and INaL _control represent INaL recorded in the presence or absence of compound, respectively.

Results from this assay relating to percent inhibition of INaL at hNaV1.6 (measured using a procedure similar to described above but using HEK-293 cells expressing recombinant, human NaV 1.6 (h NaV 1.6) at 1 pM are summarized in Table 1 below. In this table, “A” indicates inhibition of less than 30%; “B” indicates inhibition of between about 30% to about 70%; and “C” indicates inhibition of greater than 70%. “N/A” indicates not available.

TABLE 1 Compound No. NaV 1.6 Assay Data I-1 C I-2 B I-3 B I-4 B I-5 B I-6 B I-7 B I-8 B I-9 B I-10 B I-11 B I-12 B I-13 B I-14 B I-15 B I-16 B I-17 A I-18 B I-19 B I-20 B I-21 A I-22 A I-23 A I-24 A II-1 A II-2 A II-3 B II-4 A II-5 A II-6 A II-7 B II-8 B II-9 B II-10 C II-11 B II-12 C II-13 B II-14 B II-15 B II-16 N/A III-1 C III-2 C III-3 C III-4 B III-5 B III-6 B III-7 C III-8 C III-9 B III-10 A III-11 B III-12 B III-13 C III-14 B III-15 C III-16 C III-17 A III-18 A III-19 A III-20 B

While we have described a number of embodiments, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art. 

The invention claimed is:
 1. A compound having Formula (II-II):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R¹ is halo; R² is C₁₋₄ haloalkyl; R³ is H or C₁₋₄ alkyl; R⁴ is H or C₁₋₄ alkyl; or R³ and R⁴, taken together with the carbon atom to which they are attached, form a C₃₋₆ carbocyclyl; R⁵ is C₁₋₄ alkyl; and t is 0 or
 1. 2. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R¹ is F.
 3. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R² is CF₃.
 4. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R³ is CH₃; and R⁴ is CH₃.
 5. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R³ and R⁴, taken together with the carbon atom to which they are attached, form a cyclobutyl.
 6. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R⁵ is CH₃ or CH₂CH₃.
 7. The compound of claim 1, or a stereoisomer thereof, wherein the compound, or stereoisomer thereof, is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.
 9. A method for modulating sodium ion channel activity in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.
 10. The method of claim 9, wherein the subject has a condition relating to aberrant function of a sodium ion channel selected from the group consisting of a neurological disorder and a psychiatric disorder.
 11. The method of claim 10, wherein the neurological disorder or psychiatric disorder is epilepsy or an epilepsy syndrome.
 12. The method of claim 9, wherein the subject has a condition relating to aberrant function of a sodium ion channel selected from the group consisting of autosomal dominant nocturnal frontal lobe epilepsy, a benign familial neonatal-infantile seizure, cryptogenic pediatric partial epilepsy with a SCN3A mutation, Dravet syndrome, epileptic encephalopathy, focal epilepsy with a SCN3A mutation, generalized epilepsy with a febrile seizure, an infantile spasm, intractable childhood epilepsy with a generalized tonic-clonic seizure, a malignant migrating partial seizure of infancy, Rasmussen encephalitis, and sudden unexpected death in epilepsy (SUDEP).
 13. The method of claim 12, wherein the Dravet syndrome is Dravet syndrome with a SCN1A mutation.
 14. The method of claim 12, wherein the epileptic encephalopathy is selected from the group consisting of an epileptic encephalopathy with a SCN1A mutation, an epileptic encephalopathy with a SCN2A mutation, an epileptic encephalopathy with a SCN8A mutation, early infantile epileptic encephalopathy, KCNQ2 epileptic encephalopathy, KCNT1 epileptic encephalopathy, SCN2A epileptic encephalopathy, and SCN8A epileptic encephalopathy.
 15. The method of claim 9, wherein the subject has a trigeminal autonomic cephalalgia.
 16. The method of claim 15, wherein the trigeminal autonomic cephalalgia is selected from the group consisting of hemicrania continua, paroxysmal hemicrania, a long-lasting autonomic symptom with hemicrania, a short-lasting unilateral neuralgiform headache attack with a cranial autonomic symptom, and a short-lasting unilateral neuralgiform headache attack with conjunctival injection and tearing. 